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Calcium channel blockers for inhibiting preterm labour and birth

  1. Vicki Flenady1,*,
  2. Aleena M Wojcieszek1,
  3. Dimitri NM Papatsonis2,
  4. Owen M Stock3,
  5. Linda Murray4,
  6. Luke A Jardine5,
  7. Bruno Carbonne6

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 5 JUN 2014

Assessed as up-to-date: 12 NOV 2013

DOI: 10.1002/14651858.CD002255.pub2


How to Cite

Flenady V, Wojcieszek AM, Papatsonis DNM, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255.pub2.

Author Information

  1. 1

    Mater Research Institute - The University of Queensland (MRI-UQ), Translating Research Into Practice (TRIP) Centre, Brisbane, Queensland, Australia

  2. 2

    Amphia Hospital Breda, Department of Obstetrics and Gynaecology, Breda, Netherlands

  3. 3

    Mater Mothers' Hospital, Mater Health Services, Department of Obstetrics and Gynaecology, Brisbane, Queensland, Australia

  4. 4

    University of Tasmania, School of Medicine, Hobart, Australia

  5. 5

    Mater Mothers' Hospital, Mater Medical Research Institute, The University of Queensland, Department of Neonatology, South Brisbane, Queensland, Australia

  6. 6

    Hopital Trousseau, Department of Obstetrics and Gynecology, Paris, Paris, France

*Vicki Flenady, Translating Research Into Practice (TRIP) Centre, Mater Research Institute - The University of Queensland (MRI-UQ), Level 2 Aubigny Place, Mater Health Services, Annerley Road, Woolloongabba, Brisbane, Queensland, 4102, Australia. vflenady@mmri.mater.org.au.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 5 JUN 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Al-Qattan 2000

MethodsRandomised controlled trial, standard parallel group design.


Participants60 women in preterm labour at 24-34 weeks.

Setting: Kuwait University and Maternity Hospital, Kuwait.

Exclusion criteria: cardiac disease; abruptio placentae; hyperthyroidism; severe pre-eclampsia/eclampsia; clinical signs of infection: WCC > 15,000/ccm; and positive HVS culture; Polyhydramnios; cervix > 4 cm; any fetal pathology; breech presentation; IUFD; fetal distress; congenital malformations; ROM; multiple pregnancy.


InterventionsCCB group: nifedipine. 30 mg po initially then if uterine contractions persisted after 2 hrs a second dose of 20 mg. Following uterine quiescence 20 mg po every 6 hrs.

Control group: ritodrine, 50 µg/min. Following uterine quiescence 10 mg po every 4-6 hrs.

Both groups: maintenance therapy until 34 weeks and no rescue therapy.


OutcomesMaternal: delivery < 24 hrs; delivery < 48 hrs; delivery < 7 days; delivery < 36 weeks; maternal adverse drug reaction; maternal adverse drug reaction requiring cessation of treatment.

Neonatal: birthweight; low birthweight; admission to NICU; RDS; IVH; NEC; BPD; perinatal mortality; GA at birth.


NotesAdditional data not requested.

Sample size calculation: not reported.

Antenatal corticosteroids: yes, Dexamethasone 2 doses of 12 mg every 12 hrs.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention was not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskBlinding of intervention or outcomes not apparent. However, the outcomes were judged to be at low risk of performance and ascertainment bias.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskBlinding of intervention or outcomes not apparent and outcomes were not clearly defined.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk7 post randomisation exclusions in the ritodrine group; 2 withdrew and 5 due to side effects.

Selective reporting (reporting bias)Low riskData presented as expected.

Other biasUnclear riskUnable to determine.

Amorim 2009

MethodsRandomised controlled trial, standard parallel group design.


Participants54 women in preterm labour between 24 and 34 weeks with cervical dilatation < 4 cm and intact membranes.

Exclusion criteria: pre-eclampsia, diabetes, fetal anomaly, placental abruption, prior use of tocolytic drugs.


InterventionsCCB group: 10 mg nifedipine sublingually, repeated after 30 mins, if contractions persisted 20 mg 6 hourly.

Control group: 10 mg GTN patch, second 10 mg GTN patch applied after 6 hrs if contractions persisted.


OutcomesTime to effective tocolysis, delivery within 48 hrs, maternal adverse drug effects.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random number generation.

Allocation concealment (selection bias)Unclear riskOpaque sealed envelopes. Not reported if sequentially numbered.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk4 post-randomisation exclusions; 3 in the GTN patch group (1 developed pre-eclampsia and 1 suspected abruption, and another due to an error on GA) and 2 in the nifedipine group (due to developing pre-eclampsia).

Selective reporting (reporting bias)Low riskData presented as expected.

Other biasUnclear riskNot able to be determined.

Ara 2008

MethodsRandomised controlled trial, standard parallel group design.


Participants89 women with preterm labour (minimum 4 contractions in 30 mins and cervical dilatation < 3 cm) between 30-34 weeks' gestation with singleton pregnancy and intact membrane.
Setting: Institute of Child & Mother Health Matuail Dhaka and a private hospital.
Exclusion criteria: cervical dilatation > 3 cm, evidence of maternal infection, vaginal bleeding, severe pre-eclampsia, fetal growth restriction and oligohydramnios.


InterventionsCCB group: nifedipine. Loading dose of 30 mg (20 mg oral and 10 mg sublingually), followed by 20 mg (mode of administration not given, assumed oral) every 4-6 hrs "depending on the uterine activity". Treatment was deemed to have failed after 12 hrs from treatment commencement with no subsidence of contractions.
Control group: placebo. No details provided.


OutcomesSubsidence of contractions (maternal self-report), pregnancy prolongation for 48 hrs/7 days/until 36 weeks, maternal adverse side effects.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Lottery method" used (no further details provided).

Allocation concealment (selection bias)Unclear riskNo information provided.

Blinding of participants and personnel (performance bias)Low riskPlacebo controlled.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskNot clear, but probably low risk as the trial was placebo controlled.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
Low riskNot clear, but probably low risk as the trial was placebo controlled.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskData presented as expected.

Other biasUnclear riskNot able to determine.

Bracero 1991

MethodsRandomised controlled trial, standard parallel group design.


Participants49 women in preterm labour at 20-36 weeks.

Setting: Westchester county medical centre, New York
Exclusion criteria: ROM; multiple pregnancy.


InterventionsCCB group: nifedipine. 30 mg po initially then 20 mg every 6 hrs for 24 hrs then 20 mg every 8 hrs for 24 hrs followed by maintenance 20 mg every 8-12 hrs prn.
Control group: ritodrine, 100 µg/min increasing by 50 µg/min every 10 min prn to a maximum of 350 µg/min. Oral maintenance 10-20 mg every 4-6 hrs.


OutcomesMaternal: delivery < 48 hrs; pregnancy prolongation; maternal adverse drug reaction; maternal adverse drug reaction requiring cessation of treatment.
Fetal: fetal death.
Neonatal: admission to NICU; RDS; neonatal jaundice; neonatal sepsis; NEC; neonatal death; GA at birth.


NotesNo additional data received.
Sample size calculation: not reported.
Antenatal corticosteroids: not reported.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskNot specified entirely "envelopes chosen by individual patients".

Allocation concealment (selection bias)Low riskSealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded

Incomplete outcome data (attrition bias)
All outcomes
Low risk7 post-randomisation exclusions: 4 in the ritodrine group (2 were lost to follow-up, and 2 withdrawn due to severe side effects); and 3 in the nifedipine group (2 woman due to continuing contractions, and 1 due to suspected abruption).

Selective reporting (reporting bias)Low riskAddtional outcome data received.

Other biasUnclear riskNot able to determine.

Cararach 2006

MethodsRandomised controlled trial, standard parallel group design.


Participants80 women in preterm labour at 22-35 weeks in Barcelona, Spain.

Exclusion criteria: cervical dilatation > 5 cm; polyhydramnios; fetal anomalies; fetal distress; suspected IUGR; contraindication to the use of betamimetics; previous treatment with tocolytic in this pregnancy; ROM; multiple pregnancy.


InterventionsCCB group: nifedipine. 30 mg (10 mg s/l and 20 mg po) followed by 20 mg every 6 hrs for 48 hrs.

Control group: ritodrine, IV 100 µg/min increasing by 50 µg every 20 min up to a maximum of 350 µg/min for up to 48 hrs. Then oral maintenance 10 mg q6h until hospital discharge.

Rescue therapy: women were considered treatment failure if contractions persisted beyond 48 hrs and were then given indomethacin.

Subsequent episodes of preterm labour were treated according to the group allocation.


OutcomesMaternal: delivery < 2 hrs, delivery < 48 hrs, delivery < 7 days; delivery < 37 weeks; treatment to delivery interval; maternal adverse drug reaction; maternal adverse drug reaction requiring cessation of treatment.

Fetal: deaths.

Neonatal: RDS; neonatal deaths; GA at birth; birthweight; Apgar score < 7 at 5 min; hyperbilirubinaemia; neonatal infection.


NotesAdditional data received.
Sample size calculation: not reported.
Antenatal corticosteroids: yes, all women enrolled.
GBS protocol: no.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskNot stated apart from 1:1 randomisation.

Allocation concealment (selection bias)Low riskOpaque sealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk4 post-randomisation exclusions: 1 in the ritodrine group was lost to follow-up; and 3 in the nifedipine group were excluded (1 lost to follow-up and 2 withdrawn due to protocol violations).

Selective reporting (reporting bias)Low riskAdditional data received, no evidence of selective reporting.

Other biasLow riskNo evidence of other bias.

Fan 2003

MethodsRandomised controlled trial, standard parallel group design.


Participants61 women in preterm labour 28 to 38 weeks' gestation.

Inclusion criteria: contractions occurring once/10 mins, lasting 30 seconds for a period of at least 1 hr accompanied by a cervical dilation of 2 cm or by a rupture of the fetal membrane.


InterventionsCCB: nifedipine (n = 31) Initial oral dose 20 mg, another 20 mg if further uterine contraction after 30 mins, maximum dosage within the first hr is 40 mg. If contraction weakened, dosage changed to 20 mg every 8 hrs until gestation week 35.

Control: ritodrine (n = 30) 50 mg dissolved in grape sugar for IV injection, initial dosage 50 ug/min, increase 50 ug/min every 15 min according to uterine contraction until uterine contraction suppressed, maximum dosage 350 ug/min, stop vein injection after 12 hrs of effective dosage, change to oral dosage 30 mins before the stop of vein injection. Initial oral dosage is 10 mg/2 hrs and then 10 mg/6 hrs until gestation week 35.


OutcomesDelay in births for 48 hrs, 7 days and to 35 weeks; outcome for newborn and side effects of medication.


NotesTranslated from Chinese.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated "randomly divided".

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)High riskNot stated but unlikely to be blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot able to be determined.

Selective reporting (reporting bias)Unclear riskNot able to be determined.

Other biasUnclear riskNot able to be determined.

Ferguson 1990

MethodsRandomised controlled trial, standard parallel group design.


Participants66 women in preterm labour at 20-36 weeks' gestation.
Exclusion criteria: multiple pregnancy.


InterventionsCCB group: nifedipine. 10 mg capsule s/l repeated in 20 min oral maintenance 20 mg every 4-6 hrs.
Control group: ritodrine, 50 µg/min increasing by 50 µg 15-30 min up to a maximum of 350 µg/min. Oral maintenance 10-20 every 4-6 hrs.


OutcomesMaternal: delivery < 37 weeks; delivery < 48 hrs; maternal adverse drug reaction; maternal adverse drug reaction requiring cessation of treatment.

Fetal: fetal deaths.

Neonatal: RDS; IVH all grades; neonatal deaths.


NotesAdditional data received.
Sample size calculation: not reported.
Antenatal corticosteroids: yes.
GBS protocol: vaginal cultures and intrapartum AB for GBS positive.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Low riskSequentially numbered sealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 post-randomisation exclusions reported.

Selective reporting (reporting bias)Low riskAdditional data received, no evidence of selective reporting.

Other biasLow riskNo evidence of other bias.

Floyd 1992

MethodsRandomised controlled trial, standard parallel group design.


Participants52 women in preterm labour at 20-34 weeks defined as regular contractions at least every 10 mins accompanied by cervical change.
Exclusion criteria: women with ruptured membranes, chorioamnionitis, previous exposure to tocolytics in the current pregnancy, allergy to study medication, or any serious medical or obstetric condition which precluded treatment with the study medication.


InterventionsCCB group: nifedipine. 30 mg orally (3 x 10 mg capsules) then 20 mg orally 8 hourly until 37 weeks or birth.
Control group: IV 4 g MgSO4 over 20 mins then 4-6 hourly until uterine quiescence then oral Mg gluconate 2 g every 4 hrs until 37 weeks or birth.


OutcomesMaternal: delivery < 37 weeks and < 34 weeks; pregnancy prolongation; maternal adverse drug reaction requiring cessation of treatment.
Neonatal: birthweight; RDS, Apgar score < 7 at 5 mins, perinatal mortality, stillbirth and neonatal death.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Random number table generated by computer".

Allocation concealment (selection bias)Low risk"Consecutively numbered, sealed, opaque envelopes".

Blinding of participants and personnel (performance bias)High riskIntervention and outcome assessment not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskIntervention and outcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskNo indication of selective reporting.

Other biasLow riskNo evidence of other bias.

Ganla 1999

MethodsRandomised controlled trial, standard parallel group design.


Participants100 women with preterm labour (painful regular contractions < 10 mins apart for at least 30 mins) between 26-36 weeks' gestation and no previous tocolytics administered for 7 days.
Setting: Wadia Maternity Hospital, Parel, Mumbai.
Exclusion criteria: maternal diabetes, hyperthyroidism, cardiac disease, severe PIH, eclampsia, placental abruption, chorioamnionitis, cervical dilation > 3 cm, severe IUGR, foetal anomaly incompatible with life, fetal distress.


InterventionsCCB group: nifedipine. IV ringer lactate @ 100 mL/hr, till 5 mg sublingually nifedipine to maximum of 40 mg over 2 hrs. If contractions continued, Rx ceased (considered failure), ongoing 10 mg oral nifedipine 3 hrs after last dose and ongoing 10 mg 8 hourly for 48 hrs, then nifedipine SR 10 or 20 mg 12 hourly till 36 weeks.

Control: Isoxsuprine in 5% dextrose - started at 0.5 mg/min and increased to 10 mg/min and continued after contractions ceased for 12 hrs then 10 mg isoxsuprine IM 8 hourly for 48 hrs followed by 10-20 mg oral 8 hourly till 36 weeks.

Both groups received erythromycin, head low position and steroids x 2 then weekly till 36 weeks.


OutcomesGA at delivery, pregnancy prolongation for 48 hrs/until 36 weeks, maternal and fetal side effects including hyaline membrane disease +/- requiring cessation, "failure of treatment", GA at treatment, Apgar scores, birthweight, neonatal death.


NotesStudy is housed on a website sponsored by Dr Reddy's Laboratories, a global pharmaceutical company based in Hyderabad, India.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomly allotted to two groups" (no other details provided).

Allocation concealment (selection bias)Unclear riskNo information provided.

Blinding of participants and personnel (performance bias)High riskUnblinded. Differing treatment regimens (dose and mode of administration).

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskIntervention and outcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskIntervention and outcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot able to be confidently determined.

Selective reporting (reporting bias)High riskPregnancy prolongation for 48 hrs/until 36 weeks, hyaline membrane disease not reported as expected. Treatment "success" and "failure" reported only. Failure to achieve uterine relaxation or development of significant side in mother or fetus was considered treatment "failure" and treatment "success" was only reported as the inverse of this. Paper concludes that perinatal mortality is reduced by nifedipine when this outcome is not reported in the results.

Other biasUnclear riskAuthors report that patients in the groups were "well matched" on various characteristics at baseline but no information on statistical significance provided.

Garcia-Velasco 1998

MethodsRandomised controlled trial, standard parallel group design.


Participants52 women in preterm labour at 26-34 weeks.
Exclusion criteria: women with ruptured membranes, multiple pregnancy.


InterventionsCCB group: nifedipine. 10 mg s/l and 20 mg po then 10-20 every 4-6 hrs prn. If after 12 hrs of tocolysis uterine activity was present or treatment was not well tolerated this was considered tocolysis failure.
Control group: IV ritodrine, 50 µg/min increasing by 50 ug every 20 min to max of 350 µg/min maintained for 12 hrs. Oral maintenance 5 mg every 3 hrs.
Both groups: indomethacin given for continued uterine activity after 12 hrs or if treatment was not well tolerated.


OutcomesMaternal: delivery < 48 hrs; delivery < 37 weeks; pregnancy prolongation; maternal adverse drug reaction requiring cessation of treatment; maternal length of hospital stay.
Neonatal: birthweight; admission to NICU; RDS.


NotesAdditional data received.
Sample size calculation: yes - based on change in maternal BP and pulse.
Antenatal corticosteroids: yes.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number table.

Allocation concealment (selection bias)Unclear riskSealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAdditional data received, no evidence of selective reporting.

Other biasLow riskNo evidence of other bias.

George 1991

MethodsRandomised controlled trial, standard parallel group design.


Participants25 women in with a singleton pregnancy 28 to 36 weeks' gestation in preterm labour; 14 in nifedipine group and 11 in isoxsuprine group.

Inclusions: contractions occurring at least once every 10 mins and lasting for 30 seconds or more on external tocography and cervical dilation less than 2 cm.

Exclusions were: ruptured membranes, intrauterine infections, malformed fetus, hydramnios, and medical complications.


InterventionsCCB: nifedipine (initially 30 mg, followed by 20 mg every 8 hrs for 48 hrs orally).

Control: isoxuprine (40 mg in 500 mL of D5W was started at a drip rate of 30 drops/min and accelerated with close monitoring for 4 hrs. Then administered intramuscularly at 30 mg/24 hrs for 2 days.


OutcomesProlongation of pregnancy for 48 hrs from beginning of therapy, maternal blood pressure and pulse rate, and fetal heart rate.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)Unclear riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskUnclear. Minimal data reported.

Other biasUnclear riskNot able to be determined.

Glock 1993

MethodsRandomised controlled trial, standard parallel group design.


Participants100 women in preterm labour less than 34 weeks' gestation.
Exclusion criteria: multiple pregnancy; ROM; tocolysis this pregnancy; maternal medical complications; congenital malformations; IUGR.


InterventionsCCB: nifedipine 10 mg s/l repeated prn every 20 min to max of 40 mg in first hr. Once contractions ceased 20 mg every 4 hrs for 48 hrs, then maintenance 10 mg every 8 hrs until 34 weeks.

Control group: MgSO4 load 6 g IV over 30 min then 2 g/h IV up to 4 g/h as required for 24 hrs, then weaned at 0.5 g every 4-6 hrs, then maintenance therapy of oral terbutaline 5 mg every 6 hrs until 34 weeks.


OutcomesMaternal: delivery < 48 hrs; delivery < 37 weeks; delivery < 34 weeks; pregnancy prolongation index; maternal adverse drug reaction requiring cessation of treatment.
Neonatal: birthweight; perinatal mortality.


NotesSample size calculation: no.
Antenatal corticosteroids: yes.
GBS protocol: vaginal culture and intrapartum AB for GBS positive.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDoes not state exactly how randomised.

Allocation concealment (selection bias)Low riskSealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk20 post enrolment/pre-randomisation exclusions reported. No post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskNo indication of selective reporting.

Other biasLow riskNo evidence.

Jaju 2011

MethodsRandomised controlled trial, standard parallel group design.


Participants120 women in preterm labour (4 contractions in 20 min with cervical dilatation of 1 cm and effacement of > 80%) with singleton pregnancy and vertex presentation 28-36 weeks. Intact membrane and cervical dilatation no greater than 3 cm.
Setting: Shri. B. M. Patil Medical College Hospital and Research Centre, Bijapur, India.
Exclusions: APH, PIH, congenital anomaly, IUG retardation, bronchial asthma, diabetes mellitus, cardiovascular diseases, severe anaemia, hydramnios, chorioamnionitis.


InterventionsCCB group: nifedipine. Loading dose of 30 mg orally with 20 mg given orally if contractions did not subside after 90 min. Maintenance dose of 20 mg orally every 8 hrs till 37 weeks or till delivery. Treatment was deemed to have "failed" if contractions had not subsided 60 min after the second dose.
Control group: 100 mg IV ritodrine (2 x 50 mg ampoules in 500 mL ringer lactate). 50 µg/min IV ritodrine increased by 50 µg every 15 min till contractions stopped with maximum of 350 µg/min. IV ritodrine for 24 hrs after contractions stopped. 10 mg oral ritodrine (tablet) given 30 min before stopping IV drip and continued every 6 hrs until 37 weeks or delivery.


OutcomesPregnancy prolongation to 48 hrs/7 days until 37 weeks, maternal drug side effects, treatment failure, GA at birth, Apgar scores, neonatal outcomes.


NotesMean age of women in the control group reported to be "2".


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAllocations conducted "by simple randomisation technique". No further details given.

Allocation concealment (selection bias)Unclear riskNo information provided.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskIntervention and outcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskIntervention and outcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAll outcomes reported as expected.

Other biasUnclear riskGroups reported to be similar in terms of age, gestation at entry, and parity but no data given bar > .05 P value. Mean maternal age for ritodrine group reported to be "2". Not able to adequately determine due to erroneous data.

Janky 1990

MethodsRandomised controlled trial, standard parallel group design.


Participants62 women in preterm labour at 28-36 weeks' gestation.
Exclusion criteria: chorioamnionitis and maternal medical conditions, cervix > 4 cm, ROM after 34 weeks.


InterventionsCCB group: nifedipine. 10 mg s/l then 20 mg every 8 hrs. Ceased after 7 days.
Control group: IV ritodrine, 200 to 300 µg/min until contractions ceased then 100 µg/min for 24 hrs then oral maintenance 20 mg 4-6 hrs for 6 days.


OutcomesMaternal: pregnancy prolongation; maternal adverse drug reaction requiring cessation of treatment.

Fetal: fetal death.
Neonatal: birthweight; neonatal death.


NotesAdditional data received.
Sample size calculation: not reported.
Antenatal corticosteroids: not reported.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDoes not state exactly how.

Allocation concealment (selection bias)Unclear riskSealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAdditional data received, no evidence of selective reporting.

Other biasLow riskNo evidence of other bias.

Jannet 1997

MethodsRandomised controlled trial, standard parallel group design.


Participants90 women in preterm labour 25 to 35.5 weeks.
Exclusion criteria: multiple pregnancy; ROM; maternal medical conditions; standard contraindications to tocolytic.


InterventionsCCB group: IV nicardipine 3 mg/h for 2 hrs increasing prn up to a maximum of 6 mg/h until contractions cease then oral 20 mg every 8 hrs until 37 weeks.
Control group: IV salbutamol 150 µg/h, increasing after 2 hrs to 300 µg/h maintained for 48 hrs then oral maintenance 8 mg every 6 hrs po and 2 rectal suppositories of salbutamol 2 mg daily until 37 weeks.


OutcomesMaternal: delivery < 37 hrs; delivery < 34 weeks; maternal adverse drug reaction; GA at birth.
Neonatal: birthweight; admission to NICU.


Notes4 post randomisation exclusions (2 in each group).
Sample size calculation: no.
Antenatal steroids: not reported.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDoes not state exactly how, states randomised.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskUnclear, although data appears to be reported as expected.

Other biasUnclear riskNot able to determine.

Kara 2009

MethodsRandomised controlled trial, standard parallel group design.


Participants77 women with a singleton pregnancies in threatened preterm labour (painful and palpable contractions < 10 mins apart of 30 seconds duration) with or without cervical dilatation and effacement, between 20-36 weeks' gestation.
Setting: Agri Women’s and Children’s Hospital, Agri, Turkey.
Exclusion criteria: pre-eclampsia, eclampsia, placental abruption, placenta previa, cervical dilatation > 4 cm, ruptured membranes, chorioamnionitis, fetal death, fetal distress, major fetal anomalies, IUGR, diabetes, hyperthyroidism, cardiovascular diseases, uterine leiomyoma, multiple gestation, and polyhydramnios.


InterventionsCCB group: nifedipine. Initial dose of 10 mg oral (sublingual) capsule. Additional 10 mg dose sublingual given with no subsidence of contractions after 20 mins and repeated every 20 mins until contractions subsided with a maximum dose of 40 mg within the first hr. 20 mg oral nifedipine administered every 4 hrs after uterine activity subsided and continued up to 48 hrs. Maintenance therapy of 10 mg every 8 hrs until the end of 36th week.

Control group: MgSO4. Initial dose of 6 mg MgSO4 in 150 mL of 5% dextrose bolus IV administered over 20 mins. Maintenance therapy of 24 mg MgSO4 in 1000 mL of 5% dextrose at 2 g/hr increased to a maximum of 4 g/hr until contractions subsided or side effects occurred. Maintained for 24 hrs after contractions subsided, then 5 mg oral terbutaline tablets every 4-6 hrs until the end of the 36th week.


OutcomesPregnancy prolongation for 48 hrs/7 days/until 36 weeks, GA at birth, days of pregnancy prolongation, maternal and fetal side effects, birthweight, Apgar scores, stillbirth, and neonatal death.


NotesFurther information on method of randomisation is awaited from the authors.

No antenatal corticosteroids administered in either group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated "randomly" included in the study groups.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)Unclear riskBlinding not performed.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskMinimal neonatal data reported.

Other biasLow riskNone identified.

Kashanian 2005

MethodsRandomised controlled trial, standard parallel group design.


Participants80 women with GA between 26 and 34 weeks documented by a definite LMP and sonography in the first trimester. Preterm labour defined as 4 contractions in 20 min or 8 in 60 min, cervical dilation of 1 cm or greater and cervical effacement of 50% or more. Multiple pregnancy included.

Exclusions: PROM, vaginal bleeding, fetal distress or fetal death, IUGR, a history of trauma, cervical dilation > 3 cm, systemic disorders of the mother, a known uterine anomaly and BP < 90/50.


InterventionsCCB: nifedipine 10 mg s/l every 20 mins for 4 doses, if contractions inhibited nifedipine continued po (20 mg) every 6 hrs for the first 24 hrs and then every 8 hrs for the last 24 hrs.

Control group: Atosiban 300 µg/min by IV continued for a maximum of 12 hrs or 6 hrs after the patient's contractions ceased.


OutcomesMaternal: delivery within 7 days; delivery with in 48 hrs; maternal adverse drug reactions.

No neonatal outcomes.


NotesDrug side effect distributive - some patients experienced 2-3 side effects.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "4-part, ABCD, block-random allocation was used".

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Quote: "because the two drugs are completely different in shape and form a blind study was not an option".

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskMinimal neonatal outcome data reported.

Other biasUnclear riskNot able to determine

Kashanian 2011

MethodsRandomised controlled trial, block randomisation


Participants82 nulliparous women with GA between 26 and 33 weeks documented by a definite LMP and ultrasound in the first trimester. Preterm labour defined as 4 contractions in 20 mins or 8 in 60 mins, cervical dilation of 1 cm or greater and cervical effacement of 50% or more.

Exclusion criteria: multiple pregnancy, PROM, vaginal bleeding, fetal distress or fetal death, IUGR, a history of trauma, cervical dilation > 4 cm, systemic disorders of the mother including pre-eclampsia, a known uterine anomaly, smoking, other drug use, fetal anomaly, polyhydramnios, oligohydramnios, suspicion of intrauterine infection, previous use of tocolytic and BP < 90/50.


InterventionsCCB group: nifedipine. 10 mg orally every 20 mins till contractions ceased or dose of 40 mg total, then 20 mg 6 hourly for 24 hrs, then 20 mg 8 hourly for 24 hrs then 10 mg 8 hourly for 24 hrs.

Control group: 100 mg indomethacin suppository, repeated after 1 hr if contractions continued, maximum dose of 200 mg


OutcomesMaternal: cessation of contractions after 2 hrs, delivery within 48 hrs, delivery within 7 days, adverse drug reactions. Neonatal death - reported but not prespecified.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlock randomisation, 4 part, ABCD.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 women in nifedipine group excluded post-randomisation due to hypotension, 1 woman in indomethacin group excluded - not explained.

Selective reporting (reporting bias)Unclear riskMinimal neonatal outcome data reported.

Other biasUnclear riskNot able to determine.

Klauser 2012

MethodsRandomised controlled trial, 3-arm design.


Participants276 women with “idiopathic preterm labor" with intact membranes and singleton or twin pregnancy between 20-32 weeks. Vertex presentation, sufficient effacement, decrease in station. Preterm labour defined as regular contractions < 5 min apart, with cervical dilatation of 1-6 cm or dilatation altered from the previous IE.
Setting: The University of Mississippi Medical Center, USA.
Exclusion criteria: significant medical/surgical reasons for early delivery including severe pre-eclampsia, placental abruption, fetal malformations inconsistent with life, chorioamnionitis, IUGR (< fifth percentile), non-reassuring FHR, maternal non-consent to randomisation.


InterventionsCCB group: nifedipine. 30 mg orally then 20–30 mg every 4–6 hrs until contractions stopped.
Control group: indomethacin. 100 mg rectal suppository repeated up to once after 2 hrs if contractions continued. Then 50 mg oral indomethacin every 6 hrs for 12 hrs until contractions ceased. Total treatment cycle of 48 hrs. 20 mg oral twice per day. 20 mg oral pepcid given twice per day to minimise gastrointestinal symptoms.
Control group: 6 g IV MgSO4 over 20 mins, maintained at 4-6 g per hr till 1-2 hrs after contractions ceased.
All arms: no maintenance therapy, no antibiotics and no antenatal steroids given.


OutcomesMaternal: proportion of women undelivered after 48 hrs/7 days; delivery after 37, 34 and 30 weeks’; maternal drug side effects; tachycardia; fetal ductal constriction; oligohydramnios.
Neonatal: composite measure of "adverse neonatal morbidity" (including RDS, PDA, sepsis, IVH, PVL, NEC), GA at birth, birthweight, acidosis, days of mechanical ventilation, neonatal length of stay.


NotesFor subgroup comparisons, the authors of this review have split data from the CCB arm into 2 groups with smaller sample size, to achieve reasonably independent comparisons (i.e. (1) CCB versus MgS04, and (2) CCB versus indomethacin).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDrugs were distributed by the University pharmacy by opening consecutive opaque envelopes containing a card advising group allocation. The cards were "generated by random selection" but no details as to how. May be low risk but remains unclear.

Allocation concealment (selection bias)Unclear riskSequentially opened opaque envelopes. Probably low risk, but no details as to whether envelopes were sealed and tamper-proof.

Blinding of participants and personnel (performance bias)High riskNot blinded, diverging treatment regimens.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low risk"Those assessing outcomes were not privy to group assignment as they were not involved in their clinical care."

Blinding of outcome assessment (detection bias)
Subjective outcome measures
Low risk"Those assessing outcomes were not privy to group assignment as they were not involved in their clinical care."

Incomplete outcome data (attrition bias)
All outcomes
Low risk25 of 301 women were lost to attrition, reasons for each loss are provided (e.g. delivered elsewhere, no medications available).

Selective reporting (reporting bias)Low riskNeonatal and maternal outcomes reported in separate papers, all as expected.

Other biasLow riskNone evident.

Koks 1998

MethodsRandomised controlled trial, standard parallel group design.


Participants102 women in preterm labour at 24-34 weeks. Twin pregnancies included.
Exclusion criteria: maternal medical conditions, chorioamnionitis.


InterventionsCCB group: nifedipine. s/l 30 mg then po 20 mg every 4-12 hrs reducing to 20 mg every 8 hrs to 34 weeks prn.
Control group: IV ritodrine, 200 µg/min up to max of 400 µg/min then oral maintenance 80 mg every 8 h to 34 weeks.


OutcomesMaternal: delivery < 34 weeks; delivery < 48 hrs; delivery < 7 days; maternal adverse drug reaction requiring cessation of treatment.

Neonatal: GA at birth; birthweight; Apgar score < 7 at 5 mins; NICU admission; RDS; neonatal jaundice; neonatal death.


NotesOutcomes for a subset of trial participants (57) included in review.
Additional data received.
Sample size calculation: not reported.
Antenatal corticosteroids: yes - weekly to 32 weeks.
GBS protocol: vaginal culture and intrapartum AB for GBS positive.

Twin data accounted for.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskStated "equal random assignment".

Allocation concealment (selection bias)Low riskSealed envelopes.

Blinding of participants and personnel (performance bias)High riskNot possible, diverging treatment regimens.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskNot evident; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskBlinded assessment not evident.

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 post-randomisation exclusions.

Selective reporting (reporting bias)Low riskExtra data supplied with no conflict of published data.

Other biasLow riskNot evident.

Kose 1995

MethodsRandomised controlled trial.


Participants73 singleton pregnancies, between 22-36 gestational weeks in preterm labour.

Inclusion criteria: uterine contractions with progressive cervical dilatation and effacement.

Exclusions: cervical dilatation > 4 cm, preterm premature rupture of membranes, severe pre-eclampsia-eclampsia, placental abruption, placenta praevia, chorioamnionitis, severe fetal growth restriction, fetal death, fetal anomalies incompatible with life, multiple pregnancy, diabetes mellitus, hyperthyroidism, pregnant women diagnosed with heart disease, tocolytic agent previously used during the current pregnancy.


InterventionsCCB: oral nifedipine (52 women).

Tocolysis with nifedipine was initiated with 30 mg of nifedipine given orally. In addition, when contractions did not cease, an additional dose similar to the initial dose was given. When there was a suppression of contractions after 6 hrs a maintenance dose of nifedipine of 20 mg was given every 6 hrs. After 24 hrs the maintenance dose was reduced to 20 mg nifedipine every 8 hrs for 2 days. Maintenance nifedipine was continued with a minimum dose of 10 mg every 4 hrs until 37 weeks.

Control: IV ritodrine (21 women): 2 ampoules of ritodrine with a total of 50 mg were dissolved in 500 mL 2% dextrose resulting in a concentration of ritodrine of 0.2 mg/mL. The initial starting dose of ritodrine was 0.05 mg/min. According response, the participant received 0.05 mg/min for 15 mins or until contractions ceased. If there was no cessation of contractions the dose was increased until it reached the maximum dose of 0.35 mg/min, or until there were severe side effects. After reaching cessation of contractions the ritodrine level was decreased until a level of 0.05 mg/min and continued for 12 hrs. Maintenance treatment was oral treatment with 10 mg ritodrine tablets, 10 mg every 6 hrs was started and continued until 37 weeks.


OutcomesDeferred labour (therapy was found unsuccessful with deferred labour less than 38 hrs, greater than 38 hrs and to 37 gestational week), maternal side effects.


NotesTranslated from Turkish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomly assigned"; no further details.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
High riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskOutcomes reported as expected.

Other biasUnclear riskNot able to determine.

Kupferminc 1993

MethodsRandomised controlled trial, standard parallel group design.


Participants71 women in preterm labour at 26-34 weeks.
Exclusion criteria: women with ruptured membranes.


InterventionsCCB group: nifedipine. 30 mg po then 20 mg after 90 mins if required then maintenance 20 mg every 8 hrs until 34-35 weeks. Switch to ritodrine if contractions continue after 150 mins.
Control group: IV ritodrine 50 µg/min increasing by 15 µg every 15 mins to a maximum of 300 ug/min for 12 hrs, oral maintenance 10 mg every 3 hrs until 34-35 weeks.


OutcomesMaternal: delivery < 37 weeks; delivery < 48 hrs; delivery < 7 days; maternal adverse drug reaction requiring cessation of treatment.
Neonatal: NICU admission; RDS; neonatal death.
Fetal: fetal death.


NotesAdditional data received.
Sample size calculation: yes - based on maternal cardiovascular changes.
Antenatal corticosteroids: yes.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised list.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAdditional outcome data received.

Other biasUnclear riskNot able to determine.

Laohapojanart 2007

MethodsRandomised controlled trial, standard parallel group design.


Participants40 women with a single gestation between 24-26 weeks with preterm labour. Preterm labour defined as > or 4 uterine contractions per 20 mins, cervical dilation 1-4 cm and changing cervical effacement documented by obstetricians.

Exclusion criteria: heart disease; real disease; hypertension; chorioamnionitis; placental abruption; placental previa; pre-eclampsia; multiple pregnancy; diabetes and thyrotoxicosis.


InterventionsCCB group: nifedipine 10 mg tablet, further 10 mg given every 10 mins if contractions continued to a maximum of 40 mg within the first hr of treatment. 20 mg given after the first hr every 4-6 hrs consecutively for 72 hrs.

Control group: 10 µg terbutaline per min infusion increased by 5 µg every 10 mins until 25 µg was reached. Once uterine contractions stopped infusion was maintained for 2-6 hrs before switching to subcutaneous injections of terbutaline 0.25 mg every 4 hrs for 24 hrs.


OutcomesMaternal: delivery < 37 weeks; delivery < 7 days; delivery < 48 hrs; maternal adverse drug reactions requiring treatment cessation.

Neonatal: admission to NICU; RDS; IVH all grades; perinatal mortality; neonatal death; GA at birth; birthweight.


NotesDexamethasone < 34 weeks, 6 g IM every 12 hrs x 4 Indocid given if failed.

11 patients in the nifedipine group stopped treatment after the maximum dose of 40 mg in the first hr was reached. 1 of these patients delivered 2 hrs later and 10 were switched to terbutaline IV.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomised in blocks of 4, 6 and 8".

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk4 lost to follow-up in the terbutaline group.

Selective reporting (reporting bias)Unclear riskNot all expected neonatal outcomes reported.

Other biasUnclear riskNot able to determine.

Larmon 1999

MethodsRandomised controlled trial, standard parallel group design.


Participants122 women in preterm labour between 22-34 weeks.
Exclusion criteria: multiple pregnancy; ROM; chorioamnionitis; medical conditions; standard contraindications to tocolytics.


InterventionsCCB group: Nicardipine. 40 mg po then 20 mg 2 hrs prn up to 3 doses then oral maintenance 45 mg every 12 hrs until 37 weeks.
Control group: IV MgSO4 loading dose of 6 g then 2 g/h increasing up to a maximum of 4 g/hr prn. Oral maintenance magnesium lactate 4 tablets every 12 hrs until 37 weeks.


OutcomesMaternal: maternal adverse reaction; pregnancy prolongation.

Fetal: fetal death.
Neonatal: NICU admission; GA at birth; birthweight; neonatal death.

Additional data received for:
Maternal: delivery < 37 weeks; delivery < 34 week; delivery < 48 hrs; delivery < 7 days; maternal adverse drug reaction requiring cessation of treatment.

Neonatal: Apgar score < 7 at 5 mins; RDS.


NotesSample size calculation: yes - based on successful tocolysis at 6 hrs.
Antenatal steroids: yes, for women 24-34 weeks' gestation.
GBS protocol: all women received ampicillin awaiting results of vaginal culture for GBS, 7 day course for those GBS positive.

Addtional data and information were received from authors and included in the review.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Low riskSequentially numbered sealed opaque envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAll outcomes reported as expected; additional data received.

Other biasUnclear riskNot able to determine.

Lyell 2007

MethodsRandomised controlled trial, standard parallel group design.


Participants196 women in preterm labour between 24-33 weeks and 6 days gestation. Preterm labour defined by 2 or more contractions every 10 mins with cervical change, ruptured membranes, or 2 cm or more dilation and 80% effacement.

Exclusion criteria: placental abruption, placenta previa, non-reassuring fetal status, IUGR, chorioamnionitis, maternal medical disease.


InterventionsCCB group: nifedipine. 10 mg s/l every 20 mins for 3 doses total, followed by 20 mg po every 4 or 6 hrs based on physician judgement. Treatment continued until at least 12 hrs of uterine quiescence within the first 48 hrs.

Control group: MgSO4. 4 g bolus followed by a 2 g/hr infusion, an additional 2 g boluses allowed as needed for persistent preterm labour, as was increasing the infusion rate to 4 g/hr.


OutcomesMaternal: delivery prior to 37 weeks; delivery within 48 hrs; maternal adverse drug reactions.

Neonatal: admission to NICU; RDS; neonatal sepsis; NEC; IVH; neonatal deaths; birthweight; GA at birth; duration of stay in neonatal nursery.


NotesBetamethasone 12 mg IM x 2 IM X 2 24 hrs apart GBS prophylaxis.

PROM - Erythromycin and 500 mL hydration with lactated Ringer's solution before tocolysis.

Composite outcome of time to delivery and uterine activity.

Multiple pregnancy accounted for in denominators.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table.

Allocation concealment (selection bias)Low riskOpaque sequentially numbered envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk4 excluded before analysis, unclear from which study group.

Selective reporting (reporting bias)Low riskNone evident.

Other biasUnclear riskNot able to determine.

Mawaldi 2008

MethodsRandomised controlled trial, standard parallel group design.


Participants174 pregnant with preterm labour 24-34 weeks' gestation, preterm labour defined as 1-3 contractions per 10 mins for at least 60 mins. Cervical dilation between 0 and 3 cm for primigravidas and between 1 and 3 cm for multigravidas with cervical effacement less than 50%.

Exclusion criteria: high order pregnancy, major APH, ROM, major medical disorders, a temperature greater than 37.5 degrees celsius, BP less than 90/50 mmHg, a compromised fetus or fetus with lethal congenital anomalities, multiple pregnancy not mentioned.


InterventionsCCB group: nifedipine. 30 mg loading dose po followed by 20 mg after 90 mins, if contractions did not cease, 20 mg of nifedipine was given every 8 hrs for 48 hrs.

Control group: 0.25 mg loading dose of terbutaline s/c and repeated every 45 mins if contractions persisted and pulse < 120 BPM.


OutcomesMaternal: delivery < 48 hrs maternal adverse drug reactions; maternal length of hospital stay.

No neonatal outcomes.


NotesSample size calculation: reported.
Antenatal corticosteroids: no.
GBS protocol: no.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "Simple randomisation process".

Allocation concealment (selection bias)Unclear riskSealed envelopes used; whether opaque or sequentially numbered is unknown. Stated "Allocation concealment was ensured by having the treating physician draw a sealed envelope form a supply previously prepared and sealed by another staff member".

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskNo neonatal outcome data reported.

Other biasUnclear riskNot able to determine.

Nassar 2009

MethodsRandomised controlled trial comparing high-dose and low-dose nifedipine.


Participants102 women with singleton pregnancies, intact membranes, and active preterm labour at 24-34 weeks' gestation

Exclusion criteria: cervical dilation > 4 cm; IUGR; congenital malformations; non-reassuring fetal heart monitoring; chorioamnionitis; prior tocolysis in the current pregnancy; BP < 05/50 mmHg; maternal medical diseases (renal insufficiency, hepatic dysfunction, or cardiac disease); obstetric complications (placenta previa, abruption or hypertensive disorders of pregnancy).


InterventionsGroup 1: high-dose nifedipine, 20 mg s/l repeated in 30 mins followed by 120-160 mg slow release nifedipine daily for 48 hrs and 80-120 mg up to 36 weeks.

Group 2: low-dose nifedipine, 10 mg repeated every 15 mins to a maximum of 4 doses followed by 60-80 mg slow release daily for 48 hrs and 60 mg up to 36 weeks.


OutcomesMaternal: delivery < 37 weeks; delivery < 34 weeks; delivery < 7 days; delivery < 48 hrs; maternal adverse drug reactions; maternal adverse drug reactions requiring treatment cessation; APH; PPH; maternal length of hospital stay (days); pregnancy prolongation (days).

Neonatal: Apgar score < 7 at 5 mins; admission to NICU; RDS; neonatal jaundice; neonatal sepsis; NEC; IVH all grades; neonatal deaths; neonatal deaths excluding congenital abnormalities; GA at birth; birthweight; neonatal length of hospital stay (days).

Fetal: fetal deaths; fetal deaths excluding congenital abnormality.


NotesAdditional information received, no information on sample calculation, steroids or GBS available at this time.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated number table.

Allocation concealment (selection bias)Low riskSequentially numbered opaque envelopes.(did not state whether sealed but assumed so as trial methods were of a high quality).

Blinding of participants and personnel (performance bias)High riskNot blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskAssessment of outcomes performed by person blinded to treatment allocation, participants and trial staff not blinded to allocation after randomisation; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
Low riskAssessment of outcomes performed by person blinded to treatment allocation, participants and trial staff not blinded to allocation after randomisation.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Low riskAll outcomes reported as expected; additional data received.

Other biasLow riskNo evidence of other bias.

Padovani 2012

MethodsDescribed as "Randomised controlled trial".


Participants49 women with single gestation with preterm labour.
Setting: described as "Two hospitals in Sorocaba, Brazil" in study abstract.
Exclusion criteria: data limited - only reported as an abstract.


InterventionsCCB group: nifedipine. 20 mg orally (maintenance regimen not stated).
Control group: terbutaline. 5 mg/min IV, increased by 5 mg/min every 15 mins.


OutcomesTocolysis within 12 hrs, time needed for tocolysis, recurrence frequency, progression to preterm delivery. Maternal, fetal and neonatal adverse effects (tachycardia, bradycardia, hypotension, headache). NICU admission and duration, Apgar, complications of prematurity and neonatal death.


NotesReported as an abstract. Data not included in subgroup analyses as we cannot determine whether nifedipine was high or low dose.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to determine; study reported as an abstract only.

Selective reporting (reporting bias)Unclear riskUnable to determine; study reported as an abstract only.

Other biasUnclear riskUnable to determine; study reported as an abstract only.

Papatsonis 1997

MethodsRandomised controlled trial, standard parallel group design.


Participants185 women in preterm labour at 20-34 weeks.
Exclusion criteria: multiple pregnancy, chorioamnionitis, maternal medical conditions.


InterventionsCCB group: nifedipine. 10 mg s/l, repeated if necessary po 10 mg every 15 mins up to 40 mg in the first hr. Maintenance 60-160 mg/day up to 34 weeks.

Control group: ritodrine commencing at 383 µg/min increasing prn until cessation of contractions then decreasing depending on the time lag after which tocolysis is established (minimum 100 µg/min) and continued for 3 days.
Maintenance 40 mg po every 8 hrs up to 34 weeks in 2 of the 3 participating hospitals.


OutcomesMaternal: delivery < 37 weeks; delivery < 34 weeks; delivery < 7 days; delivery < 48 hrs; GA; maternal adverse drug reaction requiring cessation of treatment.
Fetal: fetal death.

Neonatal: NICU admission; RDS; neonatal death; Apgar score < 7 at 5 mins; neonatal jaundice; NEC; IVH; birthweight.


Notes12 exclusions in published report - additional data received and included.
Sample size calculation: yes - based on delay in delivery < 7 days.
Antenatal corticosteroids: yes.
GBS protocol: vaginal culture on admission and AB for positive GBS.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers.

Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported for short-term neonatal and maternal outcomes.

Selective reporting (reporting bias)Low riskAll outcomes reported as expected; additional data received.

Other biasLow riskNo evidence of other bias.

Rayamajhi 2003

MethodsRandomised controlled trial, standard parallel group design.


Participants67 pregnant women with threatened preterm labour 28-36 weeks, intact membranes. Multiple pregnancy included in nifedipine group.

Exclusion criteria: pre-eclampsia; eclampsia; APH; hydramnios; chorioamnionitis; cardiac history; thyroid history; advanced labour; IUGR; oligoamnios; abnormalities incompatible with life.


InterventionsCCB group: nifedipine. 500 mL crystalloid solution IV over 30-45 mins, maintenance at 100 mL/h. Maintenance dose 4-6 hrs after the last s/l dose, nifedipine 10-20 mg po, 6-8 hourly for no more than 7 days. Loading dose: nifedipine 10 mg s/l.

Control group: Isoxsuprine. 40 mg in 500 mL Ringer lactate at 0.08 mg/min, increasing the infusion rate up to 0.24 mg/min depending on the status of uterine contractions and occurrence of side effects. Maintained on oral isoxsuprine 10 mg 8 hourly for up to 7 days.


OutcomesMaternal: delivery < 37 weeks; delivery < 7 days; delivery < 48 hrs; maternal adverse drug reactions requiring treatment cessation; pregnancy prolongation (days).

Fetal: fetal deaths; fetal deaths excluding deaths from congenital abnormality (CA).

Neonatal: neonatal deaths; GA at birth; birthweight; perinatal mortality.


NotesSample size calculation: not reported.
Antenatal corticosteroids: yes, all women enrolled, 2 doses of 12 mg IM dexamethasone given 12 hrs apart.
GBS protocol: not reported although all women received oral AB.

Only 1 twin pregnancy included. No denominator reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated as "parallel randomisation".

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded. However, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk5 patients lost to follow-up (unsure from which group).

Selective reporting (reporting bias)Unclear riskVery few neonatal outcomes were reported.

Other biasUnclear riskNot able to determine.

Read 1986

MethodsRandomised controlled trial, standard parallel group design.


Participants40 women in preterm labour at 20-35 weeks.
Exclusion criteria: multiple pregnancy; chorioamnionitis; maternal medical conditions; ROM.


InterventionsCCB group: nifedipine. 30 mg po then 20 mg every 8 hrs for 3 days. ritodrine started after 2 hrs if contractions were undiminished.
Control group: ritodrine 50 µg/min increasing by 50 µg every 10 mins to a maximum of 300 µg. Maintained for 12 hrs then oral maintenance for 48 hrs.


OutcomesMaternal: delivery < 48 hrs; maternal adverse drug reaction, pregnancy prolongation.
Neonatal: birthweight.


NotesNo additional outcomes data available.
Sample size calculation: no.
Antenatal corticosteroids: not reported.
GBS protocol: not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded. However, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskExtra data requested and not supplied.

Other biasUnclear riskNot able to determine.

Salim 2012

MethodsRandomised controlled trial between January 2008 and December 2011.


Participants149 women in preterm labour (> 4 contractions lasting > 30 seconds within 30 mins, confirmed by external topography, 50% cervical effacement and < 4 cm dilatation for nulliparous women and 1-4 cm dilatation for multiparous) with intact membrane between 24-33+6 weeks. Singletons and twins included.
Setting: Emek Medical Center, Afula, Israel.
Exclusion criteria: rupture of membranes, vaginal bleeding from placenta previa or placental abruption, fever > 38°C, severe pre-eclampsia, cardiovascular or liver disease, systolic BP < 90 mm Hg, known uterine malformation, IUGR below 5th percentile, non-reassuring fetal status, antepartum diagnosis of major fetal malformations, multiple gestations of triplets or greater, fetal death.


InterventionsCCB group: nifedipine. Loading dose of 20 mg orally followed by 2 x 20 mg doses 20-30 mins apart "as needed". After 6 hrs, maintenance of 20-40 mg 4 times daily for 48 hrs.
Control group: atosiban. Loading dose of 6.75 mg IV in 0.9% sodium chloride solution, then 300 micrograms/min IV infusion in 0.9% sodium chloride solution for the first 3 hrs followed by 100 mcg/min for another 45 hrs.
Both groups: group B strep prophylactic antibiotics and corticosteroids. No maintenance therapy after 48 hrs. Cross-over of study drugs was carried out if labour progressed between 1-48 hrs or if adverse effects occurred. indomethacin given if both study drugs failed to stop progression.


OutcomesTocolytic efficacy and tolerability profile by pregnancy prolongation for 48 hrs without need for an alternate tocolytic (primary), pregnancy prolongation for 7 days without need for an alternate tocolytic, pregnancy prolongation for 48 hrs/7 days, preterm birth, interval between enrolment and delivery, maternal adverse drug effects, GA at delivery, neonatal morbidity and mortality related to prematurity.


NotesCross-over assignment used.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlocked randomisation in blocks of 10 using a "computer randomisation sequence generation program".

Allocation concealment (selection bias)Low riskNot clear. However, stated that allocations were kept "in the labor and delivery ward in a closed study box". Probably low risk as the study reports that allocations were revealed only immediately before drug administration.

Blinding of participants and personnel (performance bias)High riskNot blinded. Quote: "Because the study drugs were administered by different roots, blinding of participants or care providers was not performed".

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded. However, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 post randomisation exclusions in each study group:

Nifedipine: 2 women did not receive nifedipine; both had progressed beyond 4 cm

Atosiban: 2 women did not receive atosiban;1 progressed beyond 4 cm, and 1 withdrew.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting bias. The trial was registered in a publicly available trials registry and all expected outcomes were reported in the publication.

Other biasLow riskNone evident.

Taherian 2007

MethodsRandomised, clinical trial, table of random numbers.


Participants120 women with preterm labour between 26-36 weeks' gestation with intact membranes. Contractions ≥ 4 per 10 mins with duration of 30 seconds.

Exclusion criteria: taking other tocolytics, cervical dilatation ≥ 5 cm, pre-eclampsia, lethal fetal anomalies, chorioamnionitis, significant antepartum haemorrhage, maternal cardiac or liver diseases.


InterventionsCCB group: nifedipine. 10 mg tablet orally, repeated every 20 mins (maximum dose of 40 mg in first hr). If contractions subsided, then maintenance dose of 10-20 mg every 6 hrs. Patients were observed in the labour room for 24-48 hrs.

Control group: MgSO4. Loading dose of 4 g intravenously over 15 mins, then a maintenance dose of 2-3 g/hr infusion.


OutcomesMaternal: arresting preterm labour duration, safety, side effects, treatment failure, GA at delivery.

Neonatal: birthweight, Apgar score at 1 min and 5 mins.


NotesSome discrepancy with outcome reporting. Outcomes not specified and delivery data unclear. Results appear to be transposed in text. Side effects described, but no results. No neonatal data available. Additional information requested.

Antenatal corticosteroids: yes.

GBS prophylaxis: yes.

No mention of multiple pregnancy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table used.

Allocation concealment (selection bias)Unclear riskAllocation concealment not stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded. However, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskAdditional data requested.

Other biasUnclear riskNot able to determine.

Trabelsi 2008

MethodsProspective randomised study. Approved by hospital Ethics Committee. Signed consent before randomisation.


Participants45 (24 women in CCB group and 21 in salbutamol group) pregnant women with singleton pregnancies admitted for preterm labour, with intact membranes between 28 and 35 weeks' gestation. Preterm labour defined as persistence of at least 2 symptomatic uterine contractions, within a 10-min period, each lasting 30 seconds, cervix length reduced to 50%.

Exclusion criteria: cervix dilatation greater than 3 cm, pre-eclampsia or chronic arterial hypertension, oligohydramnios, fetal anomalies, signs of fetal distress, suspected intrauterine infection or growth restriction, placenta praevia, maternal diseases, contraindication or allergy to constituents to beta-adrenergic drugs or nicardipine.


InterventionsCCB group: Nicardipine. Initial IV infusion at a rate of 2 mg/min, increased every 30 mins until uterine contractions suppressed or intolerable side effects appeared or limit dose of 4 mg/h reached.

Control group: Salbutamol. Initial dose of 0.125 mg/h. Monitored for 6 hrs. If uterine contractions reduced after 24 hrs, then oral therapy. If contractions start, then to re-commence original IV treatment.


OutcomesMaternal: disappearance of uterine contractions, failure of tocolysis, side effects.

Neonatal weight, Apgar score at 1 and 5 mins, NICU, duration of hospitalisation, GA at birth and neonatal complications.


Notes3 women excluded post randomisation, as did not deliver at facility.

GBS protocol reported: no.

Antenatal corticosteroids reported: no.

Sample size calculation reported: no.

No additional outcomes data reported.

No data for < 28 weeks.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported "1:1 randomisation".

Allocation concealment (selection bias)Low riskSealed opaque, consecutively numbered envelopes.

Blinding of participants and personnel (performance bias)High riskNot performed.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded. However, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 patients lost to follow-up (did not birth in study hospital).

Selective reporting (reporting bias)Unclear riskUnable to determine.

Other biasLow riskNo evidence of other bias.

Valdes 2012

MethodsProspective randomised controlled trial between May 2007 and November 2008.


Participants132 consenting women with TPL (> 1 painful contractions every 10 min irrespective of cervical length and dilation and not eased by hydration at rest for 1 hr) between 23-34 weeks with singleton pregnancy, intact membrane and known GA.
Setting: The University of Chile Clinical Hospital, Barros Luco-Trudeau and El Pino Hospitals.
Exclusion criteria: IU infection, congenital fetal abnormality, placental abruption, severe IUGR, diabetes mellitus, cardiovascular disease, hyperthyroidism, other contraindications of therapy.


InterventionsCCB group: 20 mg oral nifedipine with 2nd and 3rd 20 mg dose given after 20 mins if contractions persisted. Maximum dose of 60 mg in the first hr. Maintenance therapy of 20 mg oral every 6 hrs after contractions subsided. Dose could be progressively lowered to min 10 mg after the second day, then slow-release nifedipine every 6 hrs till 48 hrs after subsidence of contractions.
Control group: continuous fenoterol IV infusion, initial dose of 1 g/min and increased every 30 mins till contractions subsided with max dose of 4 g/min. Max permitted maternal HR of 120 beats/min. Once contractions subsided, IV infusion at same dose for 12 hrs then maintenance therapy of 0.5–1 g/min till 48 hrs after subsidence of contractions.

Both groups: All mothers between 24 and 34 weeks received antenatal corticosteroids.


OutcomesPregnancy prolongation (primary), maternal adverse drug side effects, "clinical, metabolic and hemodynamic characteristics", perinatal outcomes (secondary).


NotesDenominators for some outcomes were unclear in manuscript. Further detail on outcomes was provided by the lead author for the purpose of this review. As part of correspondence, the author noted that the hospitals involved in the study did not know the randomisation schedule, that an aleatory computed system was used for randomisation, and that corticosteroids were given to mothers between 24 and 34 weeks' gestation.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation, permuted block design.

Allocation concealment (selection bias)Low riskPerformed centrally. Reported that collaborators were unaware of enrolment order (no further details given).

Blinding of participants and personnel (performance bias)High riskIntervention was not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk10 were lost to follow-up after discharge (8 in the nifedipine group and 2 in fenoterol).

Selective reporting (reporting bias)Low riskAll expected outcomes were reported.

Other biasLow riskNo evidence of other bias.

Van De Water 2008

MethodsRandomised controlled trial, standard parallel group design.


Participants93 pregnant women with imminent preterm labour between 24-34 weeks (imminent preterm labour: more than 1 uterine contraction every 10 mins for at least 1 hr).

Exclusion criteria: multiple pregnancy; intrauterine infection; congenital defects of the fetus; (partial) placental abruption; diabetes mellitus; cardiovascular diseases; hyperthyroidism and pre-eclampsia.


InterventionsCCB group: nifedipine: beginning of tocolysis, Tocolysis < 30 mins: 2 x 10 mg capsules maintenance dosage: sustained release preparation of 90 mg nifedipine per day.

If > 30 mins no tocolysis: 120 mg nifedipine capsule. Maintenance dosage: sustained release preparation of 120 mg nifedipine per day. After 48 hrs, 90 mg sustained release preparation of nifedipine once daily for 7 days.

Control group: ritodrine IV starting with 200 µg/min and increasing by 50 µg every 30 mins until tocolysis achieved, then maintained for 48 hrs. After 48 hrs ritodrine decreased to 50 µg/min, then IV ritodrine stopped and a maintenance dosage of oral Prepar retard (80 mg) 3 times daily was administered for a total duration of tocolysis of 7 days.


OutcomesMaternal: delivery < 34 weeks; delivery < 28 weeks; delivery < 7 days; delivery < 48 hrs; maternal adverse drug reactions; maternal adverse drug reactions requiring treatment cessation.

Neonatal: admission to NICU; RDS; neonatal sepsis; NEC; IVH all grades; long-term disability; neonatal length of hospital stay; duration of stay in neonatal nursery.

Additional data received on the following:

maternal: maternal sepsis; maternal death;

neonatal: neonatal positive blood cultures; ROP all grades; chronic neonatal lung disease - oxygen at 28 postnatal weeks; neonatal deaths; birthweight; IVH grade 3 and 4.


Notes28% loss to follow-up after 2 years. Small subset examined for developmental delay, authors respond no different at 2 years.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk1:1 randomisation, stratified by hospital and presence of ruptured membranes.

Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however. objective outcomes judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 lost to follow-up.

Selective reporting (reporting bias)Low riskExtra data supplied to support published data.

Other biasLow riskNot evident.

Weerakul 2002

MethodsRandomised controlled trial, standard parallel group design.


Participants90 women in preterm labour with a singleton pregnancy between 28-34 weeks' gestation.
Exclusion criteria: multiple pregnancy; ruptured membranes; previous tocolytic; cervix > 3 cm dilated; chorioamnionitis; infection; fetal distress; fetal anomalies; medical or obstetric complications.


InterventionsCCB group: nifedipine 10 mg s/l capsule crushed repeated after 15 mins then 20 mg after 30 mins to a maximum in the first hr of 40 mg. Maintenance of 60-120 mg daily for 3 days.
Control group: terbutaline IV loading of 0.25 mg, then infusion commencing at 5 µg/min increasing by 5 µg/min every 15 mins depending on contractions to a maximum of 15 µg/min. Following uterine quiescence infusion maintained for 2 hrs then subcutaneous injection 0.25 mg every 4 hrs for 24 hrs.


OutcomesMaternal: delivery after 48 hrs; delivery after 7 days; delivery after 37 weeks; pregnancy prolongation; GA at birth; maternal adverse drug reaction.

Neonatal: birthweight.

Additional data received on the following:
Maternal: delivery < 48 hrs; delivery < 7 days; delivery within 37 weeks; delivery < 34 weeks; use of antenatal steroids;
Maternal sepsis, maternal death, APH, PPH.

Neonatal: Apgar score < 7 at 5 mins; admission to NICU; neonatal mechanical ventilation, jaundice, sepsis, NEC, IVH, ROP; perinatal death.


NotesAdditional information on methods and outcomes data were received.
Sample size calculation: yes - no details given.
Antenatal corticosteroids: yes - all women enrolled.
GBS protocol: no.

1 post-randomisation exclusion in the other tocolytic group (terbutaline) due to patient transfer to private hospital.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random table.

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
High riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 post-randomisation exclusion.

Selective reporting (reporting bias)Low riskExtra data supplied that supported published data.

Other biasLow riskNo evidence of other bias.

Zhang 2002

MethodsRandomised controlled trial.


Participants84 women in preterm labour between 28 and 35 weeks' gestation.

Inclusion: premature labour defined as contractions 1 in 10 mins for 1 hr, or lasting for 30 seconds or longer or cervical dilation of 1 to 2 cm.

Exclusions; severe fetal growth restriction, congenital abnormality, signs of uterine infections, cervical dilation greater than 3 cm, allergy, diabetes, cardiac condition or other contraindication to nifedipine, placental abruption, pre-eclampsia, intrauterine asphyxia.


InterventionsGroup A (n = 28): nifedipine 10 mg orally. In 30 mins if still contracting a further 20 mg was given to a maximum of 40 mg. Maintenance of 10 mg every 8 hrs was continued until 35 weeks' gestation.

Group B (n = 28): nifedipine 20 mg orally. In 30 mins if still contracting a further 20 mg was given to a maximum of 40 mg. Maintenance of 20 mg every 8 hrs was continued until 35 weeks' gestation.

Group C (n = 28): no tocolysis. Luminal given for anxiety if required.


OutcomesProlongation of pregnancy, birth outcomes and maternal side effects.


NotesAll women received antenatal corticosteroids; IM dexamethasone 10 mg daily for 2 days.

Article was translated from Chinese.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated "randomly divided"; no further details.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)High riskIntervention not blinded.

Blinding of outcome assessment (detection bias)
Objective outcome measures
Low riskOutcome assessment not blinded; however, objective outcomes were judged to be low risk.

Blinding of outcome assessment (detection bias)
Subjective outcome measures
Unclear riskOutcome assessment not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions or losses at follow-up reported.

Selective reporting (reporting bias)Unclear riskUnable to assess.

Other biasUnclear riskUnbale to assess.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Al-Omari 2006Quasi-random allocation to treatment.

Breart 1979Did not assess a calcium channel blocker (the intervention was ritodrine versus ifenprodit).

Carr 1993Trial of maintenance tocolytic therapy.

Chawanpaiboon 2011The comparison group was not another tocolytic.

Dasari 2007Psychotherapeutic interventions for women in preterm labour.

Dunstan-Boone 1990Quasi-random allocation to treatment.

El-Sayed 1998Trial of maintenance tocolytic therapy.

Husslein 2007Trial comparing atosiban with clinician choice of 1 or more other tocolytics.

Junejo 2008Quasi-experimental design.

Juon 2008Pharmacokinetic study of nifedipine.

Maitra 2007Quasi-random allocation to treatment.

Malik 2007Quasi-random allocation to treatment.

Meyer 1990Women were eligible for trial entry only after subcutaneous terbutaline failed to stop regular uterine contractions and the numbers in each group (34 versus 24) raise concerns about the randomisation process.

Papadopoulos 1997Quasi-random allocation to treatment.

Piovano 1985Trial tested the addition of a calcium channel blocker for women receiving tocolysis with a betamimetic agent.

Rodriguez-Escudero 1981Trial tested the addition of a calcium channel blocker for women receiving tocolysis with a betamimetic agent.

Shim 2006Did not use calcium channel blockers.

Smith 1993Quasi-random allocation to treatment.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Chong 1991

MethodsControlled study.

ParticipantsPregnant women in preterm labour (details not specified).

InterventionsGroup 1: nifedipine (doses not specified).

Group 2: ritodrine (doses not specified).

OutcomesLag time, success rate, Apgar score of neonates before 34 weeks of gestation, maternal cardiovascular side effects.

NotesAuthors have been contacted for additional data and information on method of allocation to the study interventions.

de Heus 2009

MethodsRandomised controlled study.

Participants40 women between 25-33 weeks' gestation with preterm labour requiring tocolytic treatment not previously treated with tocolytics. Exclusion criteria: multiple pregnancy, severe vaginal bleeding, fetal congenital anomaly and signs of uterine infection.

InterventionsCCB group: nifedipine. Capsules of 10 mg given 4 times 15 min apart followed by 30 mg slow-release at 8 hrs apart up to 48 hrs.

ORA group: atosiban. 6.75 mg in 0.9 mL 0.9% sodium chloride (single bolus dose, IV) followed by infusion 300 µg/min in 5% dextrose for 3 hrs, then 100 µg/min in 5% dextrose up to 48 hrs.

OutcomesPrimary outcomes: effects of the tocolytics on fetal heart rate and its variation.

Secondary outcomes: effects of the tocolytics on fetal movement and blood flow parameters.

NotesWhile the trial was not designed to measure any of the prespecified clinical outcomes of this review, additional outcome data which may be available has been requested from the authors.

Dubay 1992

MethodsControlled study.

Participants300 newborns, born to mothers who received nifedipine or isoxsuprine.

InterventionsGroup 1: nifedipine (mothers given 30 mg stat orally and then 20 mg 8 hourly for 3 days).

Group 2: Isoxsuprine (mothers given 120-150 mg per minute (60 mg/540 mL in 5% dextrose at rate of 15-20 drops per minute and was increased by 50-75 mg per minute every 15 minutes till uterine activity ceased).

OutcomesApgar score and birthweight of infants, side effects.

NotesAuthors have been contacted for additional data and methods of allocation to the study interventions.

Haghighi 1999

MethodsControlled study (random selection).

Participants74 pregnant women with singleton pregnancies at 23-26 weeks in preterm labour.

InterventionsGroup 1: nifedipine (10 mg orally every 20 minutes if contractions persisted, up to a maximal dose of 40 mg during first hour of treatment). If contractions stopped then oral therapy with 20 mg of nifedipine was initiated 6 hrs after the last sublingual capsule and this dose was repeated at 6-hourly intervals during first 24 hrs and 20 mg every 8 hrs on second day.

Group 2: magnesium sulphate (IV loading dose of 6 g over 15 min followed by an infusion of 2 g/hr increasing to a max rate of 4 g/hr as needed to stop contractions for up to 48 hrs. Infusion continued 12 hrs after contractions ceased and then women placed on oral terbutaline 5 mg every 6 hrs. Magnesium sulphate discontinued if contracted persisted > 48 hrs or cervical dilatation > 4 cm.

OutcomesArresting uterine contractions, side effects.

NotesAuthors have been contacted for additional data and information on method of allocation to the study interventions.

Lotfalizadeh 2010

MethodsDescribed as "clinical-trial study" in study abstract.

Participants80 women in preterm labour (regular contractions < 10 mins apart, with effacement and dilatation unresponsive to pethidine, best rest and fluid therapy) between 26-34 weeks.
Setting: "obstetric clinic of Imam Reza and Ghaem hospitals".
Exclusion criteria: data limited - abstract available only.

InterventionsCCB group: oral nifedipine.
Control group: IV magnesium sulphate.

OutcomesEfficacy in pregnancy prolongation and adverse drug side effects, cost.

Notes

Mathew 1997

MethodsControlled study "random selection".

Participants60 pregnant women admitted with preterm labour.

InterventionsGroup 1: CCB- nifedipine.

Group 2: isoxsuprine hydrochloride.

OutcomesTocolysis, prolongation of pregnancy (days), maternal side effects, birthweight.

NotesAuthors have been contacted for additional data and information on method of allocation to the study interventions.

Roy 1993

MethodsControlled trial. Unclear if randomised.

Participants40 women in preterm labour between 28 and 36 weeks' gestation. Exclusions were: multiple pregnancy, cervical dilation more than 4 cm, and major pregnancy complications.

InterventionsNifedipine: 5 mg every 8 hrs, followed by 5 mg 12-hourly maintenance until 38 weeks.

Isoxsuprine: 10 mg 8 hourly, followed by 10 mg 12 hourly until 38 weeks.

OutcomesTime from randomisation to birth, birth before 38 weeks, adverse drug reaction, births with malformations, post partum haemorrhage, caesarean section.

NotesAuthors reported that women were randomly allocated but also reported that 20 women received nifedipine and another 20 gravida and gestation period matched women received Isoxsuprine. Authors have been contacted for additional data and information on method of allocation to the study interventions.

Sharma 2000

Methods"Retrospective randomised controlled trial".

Participants560 pregnant women having gestational age below 34 weeks, who had established uterine contractions associated with cervical changes & with or without premature rupture of membranes.

InterventionsGroup 1: nifedipine orally.

Group 2: ritodrine IV.

OutcomesProlongation of pregnancy.

NotesAuthors have been contacted for additional data and information on method of allocation to the study interventions.

Sofat 1994

MethodsRandomised prospective study.

Participants70 pregnant women of preterm labour between 20-35 weeks' gestation.

InterventionsGroup 1: IV Isoxsuprine (later IM and then orally 10 mg 8 hourly for 2-3 weeks).

Group 2: nifedipine (30 mg stat orally, then 20mg 8 hourly for 3 days).

OutcomesSuppressant of labour, prolongation of pregnancy, newborn birthweight, side effects.

NotesAuthors have been contacted for additional data and information on method of allocation to the study interventions.

 
Characteristics of ongoing studies [ordered by study ID]
APOSTEL III 2011

Trial name or titleAPOSTEL III study.

MethodsMulticentre randomised controlled trial. Netherlands.

Participants500 pregnant women with threatened preterm labour between 25 and 34 weeks' gestational age.

InterventionsNifedipine: (dosage 0.10 mg fast acting then in 30 mins 10 mg fast acting, in 60 mins 20 mg nifedipine, then, 20 mg every 6 hrs up to 48 hrs) versus atosiban (dosage: bolus injection of 6.75 mg IV in 1 minute, followed by 18 mg/hour for 3 hrs followed by a maintenance dosage of 6 mg/hour for 45 hrs) for 48 hrs.

replace nifedpine dose with:
Nifedipine: (dosage 0.10 mg fast acting then in 30mins 10 mg fast acting, in 60 mins 20 mg nifedipine. Then, 20 mg every 6 hrs up to 48 hrs)

OutcomesThe primary outcome of the study will be a composite for poor neonatal outcome. This outcome will include bronchopulmonary dysplasia (BPD), periventricular leukomalacia > grade 1, intracerebral haemorrhage > grade 2, NEC > stage 1, proven sepsis and in-hospital death. Secondary outcomes will be time to delivery, gestational age at delivery, number of days on ventilation support, in NICU and total days of the baby alive outside the hospital counted from a gestational age of 37 weeks and maternal side effects.

Starting dateJuly 2011. Estimated 36 month recruitment phase and ongoing as at November 2013.

Contact informationDr. M.A. Oudijk, consultant obstetrician, Dept. of Obstetrics
UMC Utrecht. E-mail:m.a.oudijk-3@umcutrecht.nl

NotesRegistered in Dutch consortium for studies in women's health and reproductivity. http://www.studies-obsgyn.nl/home/page.asp?page_id=326

Gonzalez 2011

Trial name or titleAdministration of Nifidepine versus Atosiban in pregnant women with a threat of premature labour.

MethodsRandomised trial, standard parallel design.

ParticipantsPregnant women in the 24th and 33+6th weeks of pregnancy with threatened preterm labour according to the American College of Obstetricians and Gynaecologists (ACOG's) criteria.

Setting: Hospital Clinico Universitario de Santiago, Spain.

Exclusion criteria: prior treatment with magnesium sulphate or a different tocolytic, major fetal malformations, various maternal complications (e.g. chorioamnionitis, premature rupture of membranes, severe hypertensive disorder).

InterventionsExperimental group: nifedipine. Initial dose - 10 mg oral capsules and maintenance dose of 20 mg every 6 hrs (2 x 10 mg capsules).

Control group: IV atosiban. Initial dose - bolus injection during 1 minute plus IV infusion of 7.5 mg/mL during 3 hrs, followed by maintenance with IV infusion 7.5 mg/mL at least 18 hrs to a maximum of 45 hrs. Treatment administered for a maximum of 48 hrs for both groups.

OutcomesMaternal: Prolongation of pregnancy, duration and type of labour, adverse drug side effects

Neonatal: Intracranial haemorrhage, RDS, NEC, ROP.

Starting dateJuly 2011.

Contact informationManuel Macía Cortiñas: manuel.macia.cortinas@sergas.es / María Teresa Oreiro García: maria.teresa.oreiro.garcia@sergas.es

NotesStudy not yet open for participant recruitment.

Snyder 1989

Trial name or titleControlled trial.

MethodsNot specified.

ParticipantsWomen in preterm labour.

InterventionsNifedipine vs magnesium sulphate.

Outcomes

Starting date

Contact information

NotesNotification of an ongoing trial. No details of outcome have been found.

Vis 2009

Trial name or titleCost-effectiveness of fibronectin testing in a triage in women with threatened preterm labour: alleviation of pregnancy outcome by suspending tocolysis in early labour (APOSTEL-I trial).

MethodsRandomised controlled trial.

ParticipantsWomen in preterm labour, with intact membranes, between 24-34 weeks' gestation. Those with a short cervix (10-30 mm) and negative fibronectin will be enrolled in a randomised controlled trial of nifedipine compared with placebo.

InterventionsCCB group: nifedipine 80-120 mg over 24 hrs for total of 48 hrs.

Control group: placebo given at same time as nifedipine dosing for 48 hrs.

Both groups: corticosteroids given at attending physician's discretion.

OutcomesNumber of days to delivery truncated at 7 days after trial entry (primary), neonatal mortality and morbidity, maternal drug side effects, health-related quality of life, cost (secondary).

Starting dateNot stated. Protocol submitted to journal July 2009.

Contact informationJolande Y Vis: j.y.vis@amc.nl

Notes

 
Comparison 1. Calcium channel blockers compared with placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Birth within 48 hours after trial entry2173Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.21, 0.43]

 2 Preterm birth (before completion of 37 weeks of gestation)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Maternal adverse effects189Risk Ratio (M-H, Fixed, 95% CI)49.89 [3.13, 795.02]

 
Comparison 2. Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Birth less than 48 hours after trial entry28Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 CCB versus betamimetics
191505Risk Ratio (M-H, Random, 95% CI)0.86 [0.67, 1.10]

    1.2 CCB versus glyceryl trinitrate (GTN) patch
153Risk Ratio (M-H, Random, 95% CI)0.91 [0.22, 3.66]

    1.3 CCB versus oxytocin receptor antagonists
2225Risk Ratio (M-H, Random, 95% CI)0.92 [0.37, 2.30]

    1.4 CCB versus non-steroidal anti-inflammatory drugs
2218Risk Ratio (M-H, Random, 95% CI)0.63 [0.29, 1.41]

    1.5 CCB versus magnesium sulphate
5651Risk Ratio (M-H, Random, 95% CI)0.83 [0.61, 1.13]

 2 Very preterm birth (before completion of 34 weeks of gestation)11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 CCB versus betamimetics
6630Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.66, 0.93]

    2.2 CCB versus magnesium sulphate
4429Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.76, 1.20]

    2.3 CCB versus oxytocin receptor antagonists
1145Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.31, 1.12]

    2.4 CCB versus non-steroidal anti-inflammatory drugs
1139Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.86, 1.42]

 3 Perinatal mortality (stillbirth and neonatal death up to 28 days)232129Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.53, 1.22]

    3.1 CCB versus betamimetics
171233Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.52, 1.38]

    3.2 CCB versus magnesium sulphate
5657Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.36, 3.13]

    3.3 CCB versus non-steroidal anti-inflammatory drugs
2239Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.10, 1.51]

 4 Stillbirth18Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 CCB versus betamimetics
13934Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.15, 7.23]

    4.2 CCB versus magnesium sulphate
5657Risk Ratio (M-H, Fixed, 95% CI)2.39 [0.10, 57.18]

    4.3 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Neonatal death22Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 CCB versus betamimetics
151068Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.53, 1.75]

    5.2 CCB versus magnesium sulphate
5657Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.30, 3.00]

    5.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.4 CCB versus non-steroidal anti-inflammatory drugs
2239Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.10, 1.51]

 6 Maternal death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 CCB versus magnesium sulphate
1137Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 CCB versus non-steroidal anti-inflammatory drugs
1139Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Interval between trial entry and birth (days)13Mean Difference (IV, Random, 95% CI)Subtotals only

    7.1 CCB versus betamimetics
10830Mean Difference (IV, Random, 95% CI)4.38 [0.25, 8.52]

    7.2 CCB versus magnesium sulphate
2212Mean Difference (IV, Random, 95% CI)-1.63 [-8.80, 5.54]

    7.3 CCB versus oxytocin receptor antagonists
1145Mean Difference (IV, Random, 95% CI)5.70 [-0.96, 12.36]

 8 Gestational age at birth (completed weeks)20Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 CCB versus betamimetics
141063Mean Difference (IV, Fixed, 95% CI)0.71 [0.34, 1.09]

    8.2 CCB versus magnesium sulphate
5651Mean Difference (IV, Fixed, 95% CI)0.15 [-0.22, 0.52]

    8.3 CCB versus oxytocin receptor antagonists
1145Mean Difference (IV, Fixed, 95% CI)1.20 [0.25, 2.15]

    8.4 CCB versus non-steroidal anti-inflammatory drugs
1139Mean Difference (IV, Fixed, 95% CI)0.0 [-1.51, 1.51]

 9 Preterm birth (before completion of 37 weeks of gestation)18Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 CCB versus betamimetics
131111Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.80, 0.98]

    9.2 CCB versus magnesium sulphate
4499Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.81, 1.06]

    9.3 CCB versus oxytocin receptor antagonists
1145Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.47, 0.89]

    9.4 CCB versus non-steroidal anti-inflammatory drugs
1139Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.06]

 10 Extremely preterm birth (before completion of 28 weeks of gestation)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 CCB versus oxytocin receptor antagonists
1145Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.04, 5.03]

 11 Apgar score < 7 at 5 minutes9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 CCB versus betamimetics
6557Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.26, 1.06]

    11.2 CCB versus magnesium sulphate
2217Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.48, 2.51]

    11.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)1.85 [0.17, 20.03]

 12 Admission to NICU15Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 CCB versus betamimetics
12999Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.87]

    12.2 CCB versus magnesium sulphate
2331Risk Ratio (M-H, Random, 95% CI)1.00 [0.48, 2.08]

    12.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Random, 95% CI)0.59 [0.41, 0.85]

 13 Respiratory distress syndrome21Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 CCB versus betamimetics
161293Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.48, 0.86]

    13.2 CCB versus magnesium sulphate
4577Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.56, 1.05]

    13.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.28, 1.85]

    13.4 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.13]

 14 Chronic lung disease1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 CCB versus betamimetics
191Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Necrotising enterocolitis8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 CCB versus betamimetics
5490Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.05, 0.96]

    15.2 CCB versus magnesium sulphate
2360Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.13, 3.20]

    15.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 1.88]

    15.4 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.14, 3.42]

 16 Neonatal sepsis10Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 CCB versus betamimetics
7618Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.47, 1.11]

    16.2 CCB versus magnesium sulphate
2360Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.31, 1.63]

    16.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.24, 8.10]

    16.4 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.25, 1.75]

 17 Neonatal jaundice3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 CCB versus betamimetics
3334Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.57, 0.92]

 18 Intraventricular haemorrhage10Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 CCB versus betamimetics
7596Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.34, 0.84]

    18.2 CCB versus magnesium sulphate
2360Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.30, 1.69]

    18.3 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.09, 2.46]

    18.4 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.23, 1.61]

 19 Intraventricular haemorrhage grades 3 or 46Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    19.1 CCB versus betamimetics
6560Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.23, 1.74]

 20 Periventricular leukomalacia (PVL)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 CCB versus magnesium sulphate
1151Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    20.2 CCB versus non-steroidal anti-inflammatory drugs
1160Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.02, 6.96]

 21 Retinopathy of prematurity3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    21.1 CCB versus betamimetics
2276Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.28]

    21.2 CCB versus oxytocin receptor antagonists
1179Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.04, 5.01]

 22 Maternal adverse effects24Risk Ratio (M-H, Random, 95% CI)Subtotals only

    22.1 CCB versus betamimetics
151305Risk Ratio (M-H, Random, 95% CI)0.36 [0.24, 0.53]

    22.2 CCB versus magnesium sulphate
5604Risk Ratio (M-H, Random, 95% CI)0.52 [0.40, 0.68]

    22.3 CCB versus oxytocin receptor antagonists
2225Risk Ratio (M-H, Random, 95% CI)2.61 [1.43, 4.74]

    22.4 CCB versus non-steroidal anti-inflammatory drugs
179Risk Ratio (M-H, Random, 95% CI)1.51 [0.81, 2.79]

    22.5 CCB versus glyceryl trinitrate (GTN) patch
150Risk Ratio (M-H, Random, 95% CI)0.60 [0.23, 1.54]

 23 Discontinuation of therapy for maternal adverse effects20Risk Ratio (M-H, Random, 95% CI)Subtotals only

    23.1 CCB versus betamimetics
161217Risk Ratio (M-H, Random, 95% CI)0.22 [0.10, 0.48]

    23.2 CCB versus magnesium sulphate
3339Risk Ratio (M-H, Random, 95% CI)1.61 [0.10, 25.91]

    23.3 CCB versus oxytocin receptor antagonists
1145Risk Ratio (M-H, Random, 95% CI)2.80 [0.12, 67.68]

    23.4 CCB versus non-steroidal anti-inflammatory drugs
1139Risk Ratio (M-H, Random, 95% CI)0.84 [0.22, 3.20]

 24 Caesarean section2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    24.1 CCB versus betamimetics
1107Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.38, 1.38]

    24.2 CCB versus oxytocin receptor antagonists
1145Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.67]

 25 Duration of stay in NICU (days)3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    25.1 CCB versus magnesium sulphate
2360Mean Difference (IV, Fixed, 95% CI)-4.55 [-8.17, -0.92]

    25.2 CCB versus oxytocin receptor antagonists
1179Mean Difference (IV, Fixed, 95% CI)-5.4 [-10.84, 0.04]

    25.3 CCB versus non-steroidal anti-inflammatory drugs
1160Mean Difference (IV, Fixed, 95% CI)3.60 [-8.27, 15.47]

 26 Duration of maternal hospital stay (days)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    26.1 CCB versus betamimetics
152Mean Difference (IV, Fixed, 95% CI)0.18 [-1.04, 1.40]

 27 Behavioural-emotional problems at 9-12 years1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    27.1 CCB versus betamimetics
195Mean Difference (IV, Fixed, 95% CI)-2.0 [-6.42, 2.42]

 28 Special education at 9-12 years1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    28.1 CCB versus betamimetics
196Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.19, 3.45]

 29 Motor quality at 9-12 years1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    29.1 CCB versus betamimetics
179Mean Difference (IV, Fixed, 95% CI)-4.30 [-9.96, 1.36]

 30 Quality of life at 9-12 years: physical1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    30.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-3.00, 1.00]

    30.2 Motor
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.15, 1.15]

    30.3 Autonomy
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.57, 0.57]

    30.4 Cognitive
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.58, 1.58]

    30.5 Social
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.99, 0.99]

    30.6 Positive emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    30.7 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 31 Quality of life at 9-12 years: motor1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    31.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.15, 1.15]

    31.2 Autonomy
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.57, 0.57]

    31.3 Cognitive
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.58, 1.58]

    31.4 Social
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.99, 0.99]

    31.5 Positive emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    31.6 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 32 Quality of life at 9-12 years: autonomy1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    32.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.57, 0.57]

    32.2 Cognitive
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.58, 1.58]

    32.3 Social
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.99, 0.99]

    32.4 Positive emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    32.5 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 33 Quality of life at 9-12 years: cognitive1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    33.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)0.0 [-1.58, 1.58]

    33.2 Social
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.99, 0.99]

    33.3 Positive emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    33.4 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 34 Quality of life at 9-12 years: social1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    34.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)0.0 [-0.99, 0.99]

    34.2 Positive emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    34.3 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 35 Quality of life at 9-12 years: positive emotion1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    35.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.04, 0.04]

    35.2 Negative emotion
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 36 Quality of life at 9-12 years: negative emotion1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    36.1 CCB versus betamimetics
194Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.02, 0.02]

 37 Parent distress scores at 9-12 years1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    37.1 CCB versus betamimetics
196Mean Difference (IV, Fixed, 95% CI)-1.0 [-9.25, 7.25]

 
Comparison 3. Calcium channel blockers compared with betamimetics (subgrouped by type of CCB)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Birth within 48 hours after trial entry19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Nifedipine compared with betamimetics
191505Risk Ratio (M-H, Random, 95% CI)0.86 [0.67, 1.10]

   1.2 Nicardipine compared with betamimetics
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Very preterm birth (before completion of 34 weeks of gestation)6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Nifedipine compared with betamimetics
5544Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.66, 0.93]

    2.2 Nicardipine compared with betamimetics
186Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.05, 5.31]

 3 Perinatal mortality (fetal death and neonatal death up to 28 days)17Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Nifedipine compared with betamimetics
161188Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.53, 1.44]

    3.2 Nicardipine compared with betamimetics
145Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.01, 6.84]

 4 Interval between trial entry and birth (days)10Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Nifedipine compared with betamimetics
10830Mean Difference (IV, Random, 95% CI)4.38 [0.25, 8.52]

   4.2 Nicardipine compared with betamimetics
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 5 Respiratory distress syndrome16Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Nifedipine compared with betamimetics
161293Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.48, 0.86]

   5.2 Nicardipine compared with betamimetics
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Discontinuation of therapy for maternal adverse effects16Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Nifedipine compared with betamimetics
151172Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.11, 0.40]

    6.2 Nicardipine compared with betamimetics
145Risk Ratio (M-H, Fixed, 95% CI)0.07 [0.00, 1.13]

 
Comparison 4. Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Birth within 48 hours after trial entry5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Nifedipine compared with magnesium sulphate
4529Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.60, 1.14]

    1.2 Nicardipine compared with magnesium sulphate
1122Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.30, 4.35]

 2 Very preterm birth (before completion of 34 weeks of gestation)4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Nifedipine compared with magnesium sulphate
3307Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.78, 1.23]

    2.2 Nicardipine compared with magnesium sulphate
1122Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.25, 2.06]

 3 Perinatal mortality (fetal death and neonatal death up to 28 days)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Nifedipine compared with with magnesium sulphate
4535Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.36, 3.13]

    3.2 Nicardipine compared with with magnesium sulphate
1122Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Maternal death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Nifedipine compared with with magnesium sulphate
1137Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   4.2 Nicardipine compared with with magnesium sulphate
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Interval between trial entry and birth (days)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Nifedipine compared with with magnesium sulphate
190Mean Difference (IV, Fixed, 95% CI)-5.80 [-18.59, 6.99]

    5.2 Nicardipine compared with with magnesium sulphate
1122Mean Difference (IV, Fixed, 95% CI)0.28 [-8.37, 8.93]

 6 Respiratory distress syndrome4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Nifedipine compared with magnesium sulphate
3455Risk Ratio (M-H, Random, 95% CI)0.78 [0.56, 1.09]

    6.2 Nicardipine compared with with magnesium sulphate
1122Risk Ratio (M-H, Random, 95% CI)0.63 [0.23, 1.78]

 7 Discontinuation of therapy for maternal adverse effects3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Nifedipine compared with with magnesium sulphate
2217Risk Ratio (M-H, Random, 95% CI)1.14 [0.01, 101.65]

    7.2 Nicardipine compared with with magnesium sulphate
1122Risk Ratio (M-H, Random, 95% CI)3.41 [0.14, 82.18]

 
Comparison 5. Higher dose calcium channel blockers compared with lower dose calcium channel blockers

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Birth within 48 hours after trial entry1102Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.26, 2.27]

 2 Very preterm birth (before completion of 34 weeks of gestation)1102Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.31, 1.17]

 3 Extremely preterm birth (before completion of 28 weeks of gestation)1102Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.05, 5.78]

 4 Perinatal mortality (stillbirth and neonatal death up to 28 days)1100Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.92]

 5 Stillbirth1100Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.02, 8.64]

 6 Neonatal death1100Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.92]

 7 Maternal death1102Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Interval between trial entry and birth (days)1102Mean Difference (IV, Fixed, 95% CI)7.30 [-2.21, 16.81]

 9 Gestational age at birth (completed weeks)1102Mean Difference (IV, Fixed, 95% CI)1.30 [0.03, 2.57]

 10 Preterm birth (before completion of 37 weeks of gestation)1102Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.63, 1.10]

 11 Apgar score < 7 at 5 minutes197Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.53]

 12 Admission to NICU1100Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.31, 1.05]

 13 Respiratory distress syndrome1100Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.26, 1.65]

 14 Necrotising enterocolitis1100Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 4.39]

 15 Neonatal sepsis1100Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.23, 5.11]

 16 Neonatal jaundice1100Risk Ratio (M-H, Random, 95% CI)0.57 [0.31, 1.05]

 17 Intraventricular haemorrhage1100Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.18]

 18 Maternal adverse effects1102Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.33, 3.51]

 19 Discontinuation of therapy for maternal adverse effects1102Risk Ratio (M-H, Fixed, 95% CI)5.4 [0.27, 109.76]

 20 Duration of stay in NICU (days)1100Mean Difference (IV, Fixed, 95% CI)-4.80 [-8.73, -0.87]

 21 Duration of maternal hospital stay (days)1102Mean Difference (IV, Fixed, 95% CI)0.90 [-1.59, 3.39]