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Progestational agents for treating threatened or established preterm labour

  1. Lin-Lin Su1,*,
  2. Miny Samuel2,
  3. Yap-Seng Chong1

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 31 JAN 2014

Assessed as up-to-date: 20 JAN 2014

DOI: 10.1002/14651858.CD006770.pub3


How to Cite

Su LL, Samuel M, Chong YS. Progestational agents for treating threatened or established preterm labour. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD006770. DOI: 10.1002/14651858.CD006770.pub3.

Author Information

  1. 1

    National University of Singapore, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, Singapore, Singapore

  2. 2

    Research Triangle Institute-Health Solutions, Manchester, UK

*Lin-Lin Su, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, 5 Lower Kent Ridge Wing, Singapore, 119074, Singapore. obgsll@nus.edu.sg.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 JAN 2014

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Characteristics of included studies [ordered by study ID]
Arikan 2011

MethodsRandomised controlled trial.


Participants83 women having singleton pregnancies between 24 and 34 weeks of gestation who were admitted for threatened preterm labour with intact membranes and cervical dilatation equal to or less than 2 cm with no previous cervical cerclage.


InterventionsAll participants received ritodrine infusion for tocolysis. For the study group, micronised natural progesterone was initiated intravaginally together with ritodrine and progesterone was continued following cessation of ritodrine until delivery or 36 weeks and 6 days. The participants in the control group received no additional drug besides ritodrine.


OutcomesPrimary outcome measure was the time until delivery (latency period), gestational age at delivery and delivery rate before 37 weeks of gestation. Secondary outcome measures were birthweight, fetal umbilical artery pH value, Apgar scores, perinatal morbidity and mortality, admission to the NICU, length of NICU stay, RDS, use of a mechanical ventilator and proven sepsis.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomised according to a computer-generated number list.

Allocation concealment (selection bias)Low riskTreatment was allocated based on the computer-generated number list.

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding was not used as the authors mentioned that the preparation of a true placebo was not possible in the trial.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone of the participants who were randomised in the study was lost to follow-up.

Selective reporting (reporting bias)Low riskAll the pre-specified outcomes were addressed.

Other biasLow riskNo apparent other sources of bias.

Chawanpaiboon 2011

MethodsRandomised controlled trial.


Participants150 participants between 28 to 35 weeks of gestation who were diagnosed with threatened preterm labour.


InterventionsFirst group of 50 participants was inhibited with nifedipine; second group of 50 participants were inhibited with proluton depot an third group was admitted for bed rest.


OutcomesSuccessful cessation of uterine contraction which was defined as no contraction after inhibition for 12 hours.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskIt was mentioned that the participants were randomly allocated to each group but the method of randomisation was not mentioned.

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment was not described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskThere was no mention about blinding in the study.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no loss of follow-up to the 150 patients recruited in the study.

Selective reporting (reporting bias)Low riskThe specified outcome was addressed.

Other biasLow riskNo apparent other sources of bias.

Erny 1986

MethodsRandomised controlled trial.


Participants53 participants between 30 and 36 weeks of gestation were admitted because of the risk of premature delivery (with intact membranes).


Interventions25 women received four capsules of 100 mg of micronised progesterone (Utrogestan) each and 28 women absorbed four capsules of a placebo (single oral dose).


Outcomes1. Plasma progesterone levels after 30 mins rest and 1 hour after absorption of capsules.
2. Frequency of uterine contractions 1 hour after administration of capsules.


NotesNo apparent other sources of bias


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThis is a randomised trial but the method of randomisation was not mentioned. We wrote to the author in an attempt to obtain more details about the randomisation method but did not receive any reply.

Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not mentioned.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study - the type of intervention was randomly selected and was unknown to the woman and physician.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no incomplete outcome data. Analyses were performed on all the participants recruited for the studies.

Selective reporting (reporting bias)Low riskAll the pre-specified outcomes were addressed.

Other biasLow riskNo apparent other sources of bias.

Facchinetti 2007

MethodsRandomised controlled study.


ParticipantsPregnant women between 25 and 33 weeks + 6 days of gestation who were admitted to threatened preterm labor. 60 women were recruited between September 2004 and February 2006.


InterventionsAll women underwent standard tocolysis with atosiban (Tractocile, Ferring AG, Denmark).

Women in the intervention group received 341 mg of 17P (Lentogest, AMSA SrI, Rome, Itlay) IM every 4 days, until gestational week 36.

Control participants received no treatment with progesterone.


Outcomes1. Gestational age at parturition.
2. Cervical length throughout the observation period.
3. Birthweight.
4. Tolerance.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskMethod of randomisation: The urn method of randomisation (Wei 1988) with stratification according to clinical centre, was used to create the computer-generated randomisation sequence. A 2:1 ratio was used for the assignment of women to 17 progesterone or to placebo.

Allocation concealment (selection bias)High riskThe list was managed by a senior midwife.

Blinding (performance bias and detection bias)
All outcomes
High riskThe author specifically stated that the study was not double-blind because it was not sponsored; therefore, the preparation of true placebo (same vial, same oil without active compound) was not possible.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no incomplete outcome data. Analyses were performed on all the participants recruited for the studies.

Selective reporting (reporting bias)Low riskAll the prespecified outcomes were addressed.

Other biasLow riskNo apparent other sources of bias.

Fuchs 1960

MethodsQuasi-randomised trial.


Participants150 women with symptoms of threatened premature labour were treated during the 2-year period 1956 to 1957. 35 of these women presented with the initial presenting symptoms of rhythmic or constant pains or backache.


InterventionsWomen in the intervention group received progesterone while women in the placebo group received placebo. The dosage was 200 mg daily for 3 days, 150 mg for 2 days and then 100 mg per day. If the symptoms subsided, treatment was discontinued a week after their disappearance. Only 50 mg was given on the last day.


Outcomes1. Birthweight.
2. Time of delivery in relation to treatment.


NotesThis study was also published as an abstract (Fuchs 1959).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised trial.

Method of randomisation: women with uneven admission numbers were treated with placebo and those with even admission numbers were treated with progesterone.

Allocation concealment (selection bias)High riskAllocation of treatment based on odd or even numbers indicated that assignment of treatment could be predicted in advance.

Blinding (performance bias and detection bias)
All outcomes
Low riskThe identities of the preparations were not disclosed to the participants and staff, including the authors until the completion of the study.

Incomplete outcome data (attrition bias)
All outcomes
High riskThere was no mention about the number of participants lost to follow-up. However, the total number of women under analyses of results were less than the initial 150 participants in the study, ranging from a total of 58 women for the outcome of 'delivery during treatment', 68 for the outcome of 'delivery after treatment' and 126 for the outcome of weight distribution of the infants.

Selective reporting (reporting bias)Low riskAll the pre-specified outcomes were addressed.

Other biasLow riskNo apparent other sources of bias.

Goel 2011

MethodsProspective randomised comparative trial.


Participants25 participants in established preterm labour from 28 to 37 weeks of gestation.


InterventionsWomen received either micronised progesterone or isoxupurine as treatment for preterm labour.


Outcomes1. To review the epidemiology of preterm labour.

2. To observe the effectiveness of micronised progesterone and isoxupurine.

3. To note the maternal and fetal outcome of these.


NotesThis study was presented as a poster and not published in a journal. Data available were therefore limited.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot mentioned.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot mentioned.

Selective reporting (reporting bias)Unclear riskNot mentioned.

Other biasUnclear riskLimited data.

Noblot 1991

MethodsRandomised controlled trial.


ParticipantsThere were 44 participants in the study. All the women undergoing tocolytic treatment for threatened preterm labour occurring before 35 weeks from February to October 1987 were eligible for the study. In order to eliminate the frequent false labour, only the women presenting a change in the uterine cervix or regular uterine contractions, at least every 10 mins and persisting after 1 hour of rest, were retained.


Interventions22 women were given four capsules of 100 mg of natural micronised progesterone (Utrogestan) and 22 women were given placebo.

In addition, Ritodrine was given to all women by IV infusion at a dose of 0.2 mg/min (2 ampoules of 50 mg of Ritodrine in 500 mL of isotonic glucosed serum, with a flow of 20 drops/min).

Duration: the above dose was administered for 1 hour. Thereafter, the dose of Ritodrine was adapted to each individual evolution whilst trying: (1) to administer the lowest possible dose capable of maintaining tocolysis; (2) to interrupt as early as possible the IV administration in favour of the oral route.


Outcomes1. Duration and amount of IV and total Ritodrine administered.
2. Duration of pregnancy prolongation.
3. Duration of hospitalisation.


NotesThis study was also published in another journal (Audra 1991).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskMethod of randomisation: block randomisation (randomisation was carried out by balanced series of 6 women according to randomisation tables).

Allocation concealment (selection bias)High riskIt was stated in the article that the capsules (interventions) were distributed in random order.

Blinding (performance bias and detection bias)
All outcomes
Low riskThe flasks of capsules had been prepared by the Laboratory and were unknown to the participants and physicians (including the personnel and outcome assessors).

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no incomplete outcome data. Analyses were performed on all the participants recruited for the studies.

Selective reporting (reporting bias)Low riskAll the prespecified outcomes were addressed.

Other biasHigh riskOne participant in the placebo arm and three participants in the progesterone arm were pregnant women with multiple pregnancies. The difference in the number of multiple pregnancies in the two arms could have introduced bias to some of the outcomes, such as period of pregnancy prolongation.

Tan 2012

MethodsRandomised controlled trial.


Participants113 women diagnosed with threatened preterm labour between 22 and 35 weeks' gestation scheduled to receive nifedipine tocolysis were recruited in the study.


Interventions56 women were randomised to a single IM injection of 17 alpha hydroxyprogesterone and 56 women were randomised to placebo.


OutcomesPrimary outcomes were delivery within 48 hours and within 7 days. Secondary outcome measures included delivery before 34 weeks, delivery before 37 weeks, mode of delivery, birthweight, gestational age, Apgar score, cord pH, admission to neonatal unit, perinatal mortality, neonatal morbidity including respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, surfactant use and mechanical ventilation at up to 28 days after birth.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation sequence was generated (by PCT) using an electronic generator provided by random.org and a variable block size of 8 or 12 was used.

Allocation concealment (selection bias)Low riskTreatment was allocated based on the computer-generated randomisation sequence.

Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial agents were packaged in identical containers.
Participants and their providers were blinded as to the treatment group assignment.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk1 out of the 113 women recruited were excluded due to the gestational age of 37 weeks. However, 21 out of the 112 participants (13 randomised to 17 alpha-hydroxyprogesterone caproate and 8 to placebo) delivered in a different hospital of whom 6 were completely lost to follow-up. Outcome data of women who delivered elsewhere were limited.

Selective reporting (reporting bias)Low riskAll the prespecified outcomes were addressed.

Other biasLow riskNo other source of bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bedoya 1972This study compared the use of orciprenaline with a range of other tocolytic agents for the treatment of threatened premature labour. Progesterone was included in this range of tocolytic agents but there was no specific comparison between the use of orciprenaline with progesterone.

Benifla 1997This was a double-blind study comparing the use of progesterone and placebo in women presenting with symptoms of preterm labour. However, the outcome of the study was the effects of progesterone on liver enzymes, which was not one of the outcome measures in our review.

Breart 1979This study compared the use of 2 types of progesterone rather than compared the use of progesterone with another form of tocolytic agent.

Facchinetti 2008Progesterone was used only after the initial treatment of the preterm labour with another tocolytic agent, atosiban. Progesterone was used for maintaining the uterine quiescence rather than for treatment of the preterm labour in this study.

Szekeres-Bartho 1983Progesterone was used only after the initial treatment of the preterm labour with another tocolytic agent, a betamimetic agent. Progesterone was used for maintaining the uterine quiescence rather than for treatment of the preterm labour in this study.

 
Characteristics of ongoing studies [ordered by study ID]
Wood 2011

Trial name or titleWood S

MethodsRandomised controlled trial.

ParticipantsWomen with symptomatic premature contractions successfully arrested for at least 12 hours with tocolytics.

Women with symptoms suggestive of early preterm labour whose contractions resolve without tocolysis but are fetal fibronectin positive.

Gestational age 23 weeks to 32 weeks and 6 days.

InterventionsVaginal administration of micronised progesterone (intervention group) or placebo (comparator group) from time of randomisation to gestational age of 35 weeks and 6 days or delivery.

OutcomesPrimary outcome measure: gestational age at birth.

Secondary outcome measures:

1. Proportion of women who have preterm birth at < 35 weeks.

2. Proportion of women who have preterm birth at <37 weeks.

3. Maternal hospital length of stay.

4. Proportion of women who have hospital admission for premature labour.

5. Maternal compliance with treatment.

6. Neonatal hospital length of stay.

7. Neonatal morbidity.

8. Number of day of assisted ventilation (neonate).

9. Number of days of supplemental oxygen (for neonate).

10. Birthweight.

11. Neonatal survival to discharge home.

12. Adverse event (maternal or neonate).

Starting date

Contact informationDr Stephe Wood

Goothills Medical Centre

Calgary, Alberta, Canada T2N 4JB

Notes

 
Comparison 1. Progestational agents versus placebo

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

 1 Preterm delivery4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Delivery before 37 weeks
4293Risk Ratio (M-H, Random, 95% CI)0.62 [0.39, 0.98]

    1.2 Delivery before 35 weeks
160Risk Ratio (M-H, Random, 95% CI)0.43 [0.12, 1.50]

    1.3 Delivery before 34 weeks
162Risk Ratio (M-H, Random, 95% CI)0.62 [0.30, 1.27]

 2 Birthweight (g)2Mean Difference (IV, Random, 95% CI)Subtotals only

 3 Admission to neonatal intensive care unit2187Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.59, 1.97]

 4 Low birthweight (< 2.5 kg)1105Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.61, 1.65]

 5 Intraventricular haemorrhage1104Risk Ratio (M-H, Fixed, 95% CI)3.12 [0.13, 74.76]

 6 Necrotising enterocolitis1104Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.07, 16.18]

 7 Oxygen requirement on day 7 of life1104Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.21, 2.31]

 8 Oxygen requirement on day 28 of life1104Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.08, 2.05]

 9 Mechanical ventilation2187Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.41, 3.37]

 10 Delivery within 48 hours of intervention1110Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.38, 1.50]

 11 Perinatal mortality183Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.41]

 12 Respiratory distress syndrome183Risk Ratio (M-H, Random, 95% CI)0.93 [0.06, 14.38]

 
Table 1. Birthweight (g)

Study IDProgesterone groupPlacebo group

Noblot 19913077 (no SD/SE reported) (n = 22)2832 (no SD/SE reported) (n = 22)

Facchinetti 20073103 ± 468 (SD)2809 ± 317 (SD)

Tan 20122.62 ± 0.75 (SD)2.53 ± 0.77 (SD)

 SD: standard deviation
SSE: standard error
 
Table 2. Hospitalisation days

Study IDProgesterone groupPlacebo group

Noblot 199113.6 (n = 21)17.8 (n = 18)

 
Table 3. Pregnancy prolongation (weeks)

Study IDProgesterone groupPlacebo group

Noblot 19916.0 (n = 22)6.4 (n = 22)

 
Table 4. Frequency of uterine contraction

Study IDDefinition of uterine contractionProgesterone groupPlacebo group

Noblot 1991Frequency of uterine contractions/10 minutes D0 H1 (1 hour after admission)0.7 ± 1.26 (not clear SD or SE) (n = 22)0.22 ± -0.77 (not clear SD or SE) (n = 22)

 SD: standard deviation
SSE: standard error