Preterm labour and birth

National Guideline Alliance (UK)

Preterm labour and birth

[A] Evidence review for clinical effectiveness of prophylactic progesterone in preventing preterm labour

Authors

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 Aug.

ISBN-13: 978-1-4731-1529-3

Review question: What is the clinical effectiveness of prophylactic progesterone (vaginal or oral) in preventing preterm labour in pregnant women considered to be at risk of preterm labour and birth?

Introduction

Preterm birth is a major cause of neonatal morbidity and mortality. Children who are born preterm may also suffer long term health issues related to their early birth. Therefore, identification of measures to prevent or delay premature birth is of great importance.

Women at higher risk of preterm birth may be identified by screening using recognised risk factors. These may include a preterm birth in a previous pregnancy, a previous mid-trimester loss, a short cervix on ultrasound scan, or a variety of other risk factors. These women may benefit from interventions to try and reduce the risk of an early birth. The most common interventions offered are cervical cerclage (which was not reviewed as part of this update) or progesterone.

The aim of this evidence review is to consider the effectiveness of prophylactic progesterone treatment (with either vaginal or oral progesterone) at preventing preterm labour, for women considered to be at risk of preterm labour and birth.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual 2014. Please see the methods section of the 2015 guideline for further details. Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31^st March 2018, and thereafter in accordance with NICE’s 2018 conflicts of Interests Register (see Register of Interests).

Clinical evidence

Included studies

One Cochrane systematic review (Dodd 2013) including 9 randomised controlled trials (RCTs) was included (N=1892) (Akbari 2009, Cetingoz 2011, da Fonseca 2003, Fonseca 2007, Glover 2011, Hassan 2011, Majhi 2009, O´Brien 2007, Rai 2009). 5 further RCTs (N=2097) (Ashoush 2017, Azargoon 2016, Crowther 2017, Norman 2018, van Os 2015) were included in this systematic review. In addition, 1 individual patient data (IPD) meta-analysis (Romero 2018) including data from 5 of the included RCTs (N=974) was also included as this presented additional analysis using data unreported in the original articles (Fonseca 2007, O´Brien 2007, Cetingoz 2011, Hassan 2011, Norman 2016).

Participants consisted of women at risk of preterm labour and birth, mainly due to a history of preterm labour or due to a short cervix. No studies were found for women presenting with other risk factors for preterm labour and birth.

Some of the identified trials were suitable for meta-analyses and these have been performed as appropriate by the NGA technical team. No pooled estimates were extracted from the Cochrane review (Dodd 2013). Instead, estimates from the individual studies were extracted and used to combine with other studies as appropriate.

Pooled estimates from the IPD meta-analysis were included because individual estimates were not reported by the study authors. These results specifically included women with a short cervix (≤25 mm), therefore have been included separately as part of the subgroup analysis. The pooled estimates were not combined with other individual estimates because the results from the IPD meta-analysis would skew the variance. Where available, individual estimates from studies included in the IPD meta-analysis were extracted from the original studies and included in the overall analysis for the whole population.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review, with reasons for their exclusion, are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 2 provides a brief summary of the included studies.

Table 2

Summary of included studies.

See appendix D for clinical evidence tables and appendix E for the Forest plots.

Quality assessment of clinical studies included in the evidence review

See appendix F for full GRADE tables.

Economic evidence

A systematic review of economic literature was conducted, but no studies were identified which were applicable to this review question.

Economic model

No economic modelling was undertaken for this review.

Evidence statements

Comparison 1. Vaginal progesterone versus placebo

Critical outcomes

Preterm birth <34⁺⁰ weeks’

Eight randomised controlled trials (N=2145) provided low quality evidence to show that those who received vaginal progesterone experienced a clinically important decrease in the number of preterm births (at <34 weeks’ gestation), as compared to those who received placebo. There was inconsistency in the effect estimate across the different trials (I² = 60%), however, this resolved after conducting pre-specified subgroup analysis.

Subgroup analysis: Women with a history of spontaneous preterm birth

Five randomised controlled trials (N=507) provided moderate quality evidence to show that, for women with a history of spontaneous preterm birth, those who received vaginal progesterone experienced a clinically important decrease in preterm birth (at <34 weeks’ gestation) as compared to those who received placebo.

Subgroup analysis: Women with a short cervix (<30 mm)

Three randomised controlled trials (N=357) provided low quality evidence to show that, for women with a short cervix (<30 mm), those who received vaginal progesterone experienced a clinically important decrease in the number of preterm births (at <34 weeks’ gestation) as compared to those who received placebo.

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis of five randomised controlled trials (N=974) provided low quality evidence to show that, for women with a short cervix (≤25mm), those who received vaginal progesterone experienced a clinically important decrease in the number of preterm births (at <34 weeks’ gestation) as compared to those who received placebo.

Stillbirth

Five randomised controlled trials (N=3339) provided very low quality evidence to show that there was no clinically important difference in the number of stillbirths between those who received vaginal progesterone or placebo.

Subgroup analysis: Women with a history of spontaneous preterm birth

Two randomised controlled trials (N=1410) provided low quality evidence to show that, for women with a history of spontaneous preterm birth, there was no clinically important difference in the number of stillbirths between those who received vaginal progesterone or placebo.

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis of five randomised controlled trials (N=974) provided very low quality evidence to show that, for women with a short cervix (≤25mm), there was no clinically important difference in the number of stillbirths between those who received vaginal progesterone or placebo.

Infant mortality

Nine randomised controlled trials (N=3810) provided moderate quality evidence to show a clinically important decrease in infant mortality for those who received vaginal progesterone, as compared to placebo.

Subgroup analysis: Women with a history of spontaneous preterm birth

Three randomised controlled trials (N=1551) provided low quality evidence to show that, for women with a history of spontaneous preterm birth, there may be a clinically important decrease in infant mortality in those who received vaginal progesterone as compared to those who received placebo, but there is uncertainty around the estimate (RR 0.53, 95% CI 0.25 to 1.12).

Subgroup analysis: Women with a short cervix (<30 mm)

Three randomised controlled trials (N=812) provided low quality evidence to show that, for women with a short cervix (<30 mm), there may be a clinically important decrease in infant mortality in those who received vaginal progesterone as compared to those who received placebo, but there is uncertainty around the estimate (RR 0.42, 95% CI 0.16 to 1.08).

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis of five randomised controlled trials (N=974) provided low quality evidence to show that, for women with a short cervix ≤25 mm), there may be a clinically important decrease in infant mortality in those who received vaginal progesterone as compared to those who received placebo, but there is uncertainty around the estimate (RR 0.45, 95% CI 0.18 to 1.08).

Important outcomes

Gestational age at birth (mean weeks’)

Three randomised controlled trials (N=1908) provided very low quality evidence to show that there was no clinically important difference in gestational age at birth between those who received vaginal progesterone or placebo. These results should be interpreted with caution as there was substantial heterogeneity in the effect estimates from the individual trials (I²=82%).

Subgroup analysis: Women with a history of spontaneous preterm birth

Two randomised controlled trials (N=711) provided very low quality evidence to show that, for women with a history of spontaneous preterm birth, there was no clinically important difference in gestational age at birth between those who received vaginal progesterone or placebo. These results should be interpreted with caution as there was substantial heterogeneity in the effect estimates from the individual trials (I²=91%).

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis of five randomised controlled trials (N=974) provided moderate quality evidence to show that, for women with a short cervix (≤25 mm), there was a clinically important increase in gestational age at birth for those who received vaginal progesterone, compared to those who received placebo.

Neonatal sepsis

Six randomised controlled trials (N=1843) provided low quality evidence to show that infants of those who received vaginal progesterone experienced a clinically important decrease in the occurrence of neonatal sepsis, as compared to those who received placebo.

Subgroup analysis: Women with a history of spontaneous preterm birth

Three randomised controlled trials (N=1031) provided moderate quality evidence to show that, for women with a history of spontaneous preterm birth, infants of those who received vaginal progesterone experienced a clinically important decrease in the occurrence of neonatal sepsis, as compared to those who received placebo.

Subgroup analysis: Women with a short cervix (<30 mm)

Three randomised controlled trials (N=812) provided very low quality evidence to show that, for women with a short cervix (<30 mm), there was no clinically important difference in the occurrence of neonatal sepsis between those who received vaginal progesterone or placebo.

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis of five randomised controlled trials (N=974) provided moderate quality evidence to show that, for women with a short cervix (≤25mm), there may be a clinically important decrease in neonatal sepsis for infants of those who received vaginal progesterone as compared to those who received placebo, but there is uncertainty around the estimate (RR 0.61, 95% CI 0.34 to 1.09).

Health-related quality of life (measured with Euro-QoL-5 Dimensions health utility scores)

Change from baseline to birth

One randomised controlled trial (N=390) provided high quality evidence to show that there was no clinically important difference in health-related quality of life scores from baseline to birth, as measured with the EuroQoL-5, between those who received vaginal progesterone or placebo.

Change from baseline to 12 months

One randomised controlled trial (N=553) provided high quality evidence to show that there was no clinically important difference in health-related quality of life scores from baseline to 12 months, as measured with the EuroQoL-5, between those who received vaginal progesterone or placebo.

Health-related quality of life (measured with SF-36); women with a history of spontaneous preterm birth

General health domain

One randomised controlled trial (N=787) provided high quality evidence to show that, for women with a history of spontaneous preterm birth, there was no clinically important difference in health-related quality of life scores, as measured by the SF-36 general health domain, between those who received vaginal progesterone or placebo.

Social functioning domain

One randomised controlled trial (N=787) provided high quality evidence to show that, for women with a history of spontaneous preterm birth, those who received vaginal progesterone experienced a clinically important decrease in mean health-related quality of life score, as measured by the SF-36 social functioning domain, as compared to those who received placebo.

Emotional role domain

One randomised controlled trial (N=787) provided high quality evidence to show that, for women with a history of spontaneous preterm birth, there was no clinically important difference in health-related quality of life scores, as measured by the SF-36 emotional role domain, between those who received vaginal progesterone or placebo.

Mental health domain

One randomised controlled trial (N=787) provided high quality evidence to show that, for women with a history of spontaneous preterm birth, there was no clinically important difference in health-related quality of life scores, as measured by the SF-36 mental health domain, between those who received vaginal progesterone or placebo.

Bayley-III cognitive composite score (2 years follow-up)

One randomised controlled trial (N=833) provided high quality evidence to show that there was no clinically important difference in Bayley-III cognitive composite score at 2 years follow-up between the infants of those women who received vaginal progesterone or placebo.

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis including one randomised controlled trial (N=168) provided moderate quality evidence to show that, for infants of women with a short cervix (≤25 mm), there was no clinically important difference in Bayley-III cognitive composite score at 2 years follow-up between those who received vaginal progesterone or placebo.

Moderate or severe neurodevelopmental impairment (2 years follow-up)

One randomised controlled trial (N=782) provided moderate quality evidence to show that there was no clinically important difference in moderate or severe neurodevelopmental impairment at 2 years follow-up between the infants of those who received vaginal progesterone or placebo.

Women with a short cervix (≤25 mm)

An individual participant data meta-analysis including one randomised controlled trial (N=158) provided very low quality evidence to show that, for infants of women with a short cervix (≤25 mm), there was no clinically important difference in moderate or severe neurodevelopmental impairment events at 2 years follow-up between those who received vaginal progesterone or placebo.

Hearing impairment

One randomised controlled trial (N=931) provided low quality evidence to show that there was no clinically important difference in the number of infants with hearing impairment at 2 years follow-up between those who received vaginal progesterone or placebo.

Visual impairment

One randomised controlled trial (N=912) provided low quality evidence to show that there was no clinically important difference in the number of infants with visual impairment at 2 years follow-up between those who received vaginal progesterone or placebo.

Visual or hearing impairment (2 years follow-up); women with a short cervix (≤25 mm)

An individual participant data meta-analysis of one randomised controlled trial (N=187) provided very low quality evidence to show that, for infants of women with a short cervix (≤25 mm), there was no clinically important difference in visual or hearing impairment events at 2 years follow-up between those who received vaginal progesterone or placebo.

Comparison 2. Oral progesterone versus placebo

Critical outcomes

Preterm birth <34⁺⁰ weeks’

One randomised controlled trial (N=148) provided moderate quality evidence to show that, in those with a previous history of spontaneous preterm birth, women who received oral progesterone experienced a clinically important decrease in preterm birth (<34 weeks’ gestation) as compared to those who received placebo.

Infant mortality

Two randomised controlled trials (N=335) provided moderate quality evidence to show that, in those with a previous history of spontaneous preterm birth, women who received oral progesterone experienced a clinically important decrease in infant mortality, as compared to those who received placebo.

Important outcomes

Gestational age at birth (mean weeks’)

Two randomised controlled trials (N=220) provided moderate quality evidence to show that, for women with a history of spontaneous preterm birth, there was a clinically important increase in gestational age at birth for those who received oral progesterone, compared to those who received placebo.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The aim of this review was to assess the effectiveness and safety of prophylactic oral or vaginal progesterone in women at risk of preterm birth due to different risk factors. The committee therefore designated 3 critical outcomes: preterm birth <34⁺⁰ weeks’, stillbirth and infant mortality prior to discharge. These outcomes were selected as the most direct indicators of the efficacy and safety of prophylactic progesterone in women at risk of preterm birth.

The committee identified 4 further outcomes as important: gestational age at birth, early onset neonatal sepsis (up to 72 hours), maternal satisfaction/ health-related quality of life (HRQoL), and neurodevelopmental outcome at ≥ 18 months. These outcomes were important because a reduced gestational age can put babies at significant risk of morbidity and mortality, early onset neonatal sepsis may occur if birth takes place preterm, and women’s perceived health was also prioritised to assess the effect of the intervention on maternal satisfaction/HRQoL. As preterm birth may be associated with neurodevelopmental impairment, the committee believed it was important to include neurodevelopmental outcome at ≥18 months.

The quality of the evidence

One Cochrane systematic review, 1 IPD meta-analysis and 5 RCTs were included in this review. The quality of the evidence ranged from very low to high as assessed by the NGA technical team using GRADE.

The main reason for downgrading was the risk of bias due to studies failing to report how randomisation was performed or concealed, or because women, investigators and assessors were aware of treatment allocation. Other reasons for downgrading the quality of the evidence included high heterogeneity, which is due to differences in the studies included in a meta-analysis. Where considerable heterogeneity was present (an I-squared value of 50% or more), predefined subgroup analyses were performed to identify the effect in different subpopulations of women.

Additionally, outcomes were also downgraded because of imprecision, as the trials had few women included, and therefore the confidence intervals around the estimate for each of the outcomes were wide.

The majority of studies included in this review incorporated a broad population of women – all of whom were perceived to be at high risk of preterm birth, but often for a variety of reasons. Many women had a previous history of preterm birth, but some had other risk factors, including a short cervix, uterine malformations or previous cervical surgery. For some of the studies, it was also noted that these populations were overlapping.

Benefits and harms

Babies born before 34 weeks of gestational age are at an increased risk of complications in the immediate postnatal period and later in life. There are certain characteristics of women’s past and current pregnancies that may predispose women to preterm birth – such as a previous history of preterm birth or a short cervical length. Progesterone has been used in these women, to try and reduce the risk of an early birth. However, whether progesterone benefits all women, or only those with specific risk factors, is unclear.

The committee noted that the overall estimate showed a benefit of vaginal progesterone for women considered to be at risk of preterm birth. However, they were aware that the studies recruited women with a wide range of different risk factors, and that vaginal progesterone may be of most benefit for specific subpopulations of women.

The committee noted that the subgroup analysis for women with a previous history of preterm birth, and for women with a short cervix (≤25mm) showed an important benefit with the use of vaginal progesterone. Therefore, the committee agreed that progesterone should be offered to women with both of these risk factors.

The use of cerclage was not considered in this update, but the first recommendation in the previous version of the guideline had been a combined recommendation for progesterone and cerclage, even though the previous evidence reviews were carried out separately and did not compare progesterone to cerclage. As, following this review of the effectiveness of progesterone, the indications to offer progesterone did not change (a history of preterm birth and a short cervix) the committee therefore adopted the recommendation from the previous guideline which stated this. Also, as in the previous guideline, the committee agreed that as there was no evidence comparing progesterone and cerclage (and a research recommendation had been made in the previous guideline stating this) the choice of cerclage or progesterone should be determined after discussion between the woman and health care professionals.

Although there was evidence of benefit for progesterone in women with previous preterm birth and evidence of benefit in women with a short cervix, the committee were aware that these subpopulations of women overlapped. Therefore some women with a previous history of preterm birth will also have a cervical length ≤25mm, and some women with a cervical length ≤25mm will also have a history of preterm birth. Consequently, determining which of these two risk factors best identified women who would benefit from progesterone was not possible.

However, due to the clear improvement in outcome for women with a previous history of preterm birth (RR of preterm birth at <34 weeks 0.27 [95% CI 0.15 to 0.49]), the committee agreed progesterone should be considered for women with a history of preterm birth, even if the cervical length was not ≤25mm, or was unknown. Similarly, the IPD meta-analysis confirmed an important overall risk reduction for progesterone in women with a cervix of ≤25mm (RR 0.65 [95% CI 0.51-0.83]). Again, this analysis included women with and without a previous history of preterm birth. Therefore the committee agreed that progesterone should be considered for women with a short cervix identified on scan, but without a previous history of preterm birth. Due to the uncertainty over the benefits of progesterone in these subgroups (women who have risk factors for a preterm birth but do not have a short cervix, and women who have a short cervix but no other risk factors for preterm birth) the committee made research recommendations.

The analysis for women with a cervical length of <30mm showed a benefit to vaginal progesterone at reducing preterm birth <34 weeks. However, it was noted that the majority of the women included in this analysis actually had a cervical length which was considerably shorter than 30mm, with Hassan 2011 including women with a cervical length of 10-20mm, and Fonseca 2007 including those with a cervical length <15mm. Furthermore, the committee agreed that the normal range for cervical length in pregnancy was not well understood, but that it was known that it gradually reduced over the course of pregnancy. A cervical length of 25mm has been identified as being on or below the 5^th centile up until 24 weeks’ of gestational age by one study (Salomon 2009). Therefore, the committee agreed that 25mm represented a reasonable threshold at which to consider progesterone treatment.

The studies included in this evidence review commenced treatment with vaginal progesterone at a variety of different time points, ranging from 14 to 25 weeks. The committee agreed that it was important to provide guidance on when progesterone should be started, but noted that the evidence base for this was poor. Based on their expertise, and the time frame for starting treatment in the studies, they recommended that progesterone should be commenced between 16 and 24 weeks. The committee anticipated that women would discuss the risks and benefits of progesterone treatment (or cerclage, where appropriate) with an obstetrician, rather than their GP. Therefore, this would enable the risks and benefits of progesterone to be discussed and treatment to be commenced prior to 24 weeks, if appropriate. Similarly, it was not clear when progesterone should be stopped. The committee discussed the fact that, in their experience, it should be continued to at least 34 weeks but that the exact stoppage time remains uncertain. Because of the uncertainty about when progesterone should be started and stopped, the committee made a research recommendation to highlight that the optimal timing of treatment was unclear and should be assessed.

No subgroup analysis was possible for women with the other risk factors identified in the review protocol – preterm pre-labour rupture of the membranes, mid-trimester bleeding, previous cervical trauma or surgery or a positive fetal fibronectin test. Therefore, the committee were unable to make recommendations regarding the use of progesterone in women with these risk factors.

The committee were aware that the stimulus to update the Preterm Labour and Birth guideline was the publication of the OPPTIMUM trial - a large, UK based trial designed to identify the potential benefit of vaginal progesterone for women at risk of preterm birth. The overall conclusion of this study was that vaginal progesterone was not of benefit in the prevention of preterm birth for women with recognised risk factors. Data from the OPPTIMUM trial has been included in this evidence review, as part of the overall analyses (including women with any risk factors), and as part of the IPD meta-analysis for women with a short cervix. The reasons why the overall conclusions of the OPPTIMUM study are different to this meta-analysis are not entirely clear. However, the heterogeneity of the underlying population may well contribute. The OPPTIMUM study recruited women with a variety of risk factors for preterm birth, including previous preterm birth, cervical length ≤25mm, preterm premature rupture of the membranes or previous procedure to treat abnormal cervical smears. Data for the outcomes specified on our review protocol for these subgroups of women were not available. The OPPTIMUM trial authors have themselves highlighted the need for detailed subgroup analysis using individual participant data, to identify specific populations of women in whom progesterone may be of benefit.

Some limited evidence suggested that prophylactic oral progesterone reduced the risk of preterm birth <34 weeks, reduced the risk of infant mortality and increased gestational age in women with a history of spontaneous preterm birth. However, the committee raised some concerns regarding the conduct and applicability of the studies to the UK setting. For instance, one of the studies was conducted in Egypt and reported a neonatal mortality rate of 25% in the placebo arm. This perinatal mortality is much higher than that seen in UK practice, and may reflect more limited neonatal care facilities in other countries. Oral progesterone is currently not used routinely in UK practice, and no trials were identified which directly compared oral and vaginal preparations, therefore the committee agreed that vaginal progesterone should be the preparation of choice.

Cost effectiveness and resource use

Vaginal progesterone is a relatively inexpensive preparation, and is already recommended for use in some women at risk of preterm birth. Therefore, the recommendations are not anticipated to increase the cost of medication significantly. However, the cost of a preterm birth is very high – in terms of immediate care in the neonatal unit, long term health effects for the infant, and health related quality of life for women and their babies. As vaginal progesterone is anticipated to reduce the incidence of preterm birth this should be a valuable and cost-effective use of resources.

Other factors the committee took into account

The committee were aware that cervical scanning is not currently recommended by the National Screening Committee for all pregnant women, but they regularly review this decision. Therefore cervical length scanning is currently only offered to women in whom there is a clinical concern regarding the risk of preterm labour. Individual units will have local procedures in place to determine which, if any, women received a cervical length scan. However, the committee were aware that the document Saving Babies’ Lives (Version 2), from NHS England, provides some guidance regarding who should undergo cervical length scanning.

References

Akbari 2009
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Appendix A. Review protocols

Table 3

Review protocol for clinical effectiveness of prophylactic progesterone in preventing preterm labour.

Appendix B. Literature search strategies

Review question search strategies

Table 4

Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations.

Table 5

Databases: Embase; and Embase Classic.

Table 6

Databases: Cochrane Central Register of Controlled Trials; and Cochrane Database of Systematic Reviews.

Health economics search strategies

Table 7

Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations.

Table 8

Databases: Embase; and Embase Classic.

Table 9

Database: Cochrane Central Register of Controlled Trials.

Appendix C. Clinical evidence study selection

Figure 1Flow diagram of clinical article selection for clinical effectiveness of prophylactic progesterone in preventing preterm labour

Appendix D. Clinical evidence tables

Table 10. Clinical evidence for clinical effectiveness of prophylactic progesterone in preventing preterm labour (PDF, 509K)

Appendix E. Forest plots

Comparison 1. Vaginal progesterone versus placebo

Critical outcomes

Figure 1Preterm birth <34+0 weeks

Figure 2Stillbirth

Figure 3Infant mortality

Important outcomes

Figure 4Gestational age at birth (mean weeks)

Figure 5Neonatal sepsis

Figure 6Neonatal sepsis; women with a short cervix (<30 mm); treatment started ≥ 20 weeks gestational age

[This figure is presented separately from figure 5 because a random effects model was utilised due to high heterogeneity for this subgroup]

Comparison 2. Oral progesterone versus placebo

Critical outcomes

Figure 7Infant mortality

Figure 8Gestational age at birth (mean weeks)

Appendix F. GRADE tables

Table 11

Comparison 1. Vaginal progesterone versus placebo.

Table 12

Comparison 2. Oral progesterone versus placebo.

Appendix G. Economic evidence study selection

No economic evidence was identified for this review question.

Figure 9Economic evidence study selection

Appendix H. Economic evidence tables

No economic evidence was identified for this review question.

Appendix I. Health economic evidence profiles

No economic evidence was identified for this review question.

Appendix J. Health economic analysis

No health economic analysis was carried out for this review question.

Appendix K. Excluded studies

Table 13

Clinical studies.

Table 14

Excluded economic studies.

Appendix L. Research recommendations

1. Does progesterone reduce the risk of preterm birth in women who have risk factors for preterm birth, but do not have a short cervix (cervical length >25mm)?

Why this is important

Preterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include women with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix. There is no evidence for the effectiveness of progesterone in women who do not have a short cervix, but who do have other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for these women, and also whether measuring the cervical length to guide treatment is necessary.

Table 15

Research recommendation rationale.

Table 16

Research recommendation modified PICO table.

2. Does progesterone reduce the risk of preterm birth in women who have a cervical length ≤25mm but no history of preterm birth?

Why this is important

Preterm birth is a cause of significant morbidity for women and babies, and impacts negatively on women and their families, as well as being costly to the NHS. There is good evidence for the use of progesterone to reduce preterm birth, however studies include women with a combination of risk factors for preterm birth, such as a history of preterm birth and a shortened cervix. There is a lack of evidence for the effectiveness of progesterone in women with a cervical length ≤25mm, but without other risk factors for preterm birth. It is therefore difficult to decide if progesterone should be recommended for these women, and consequently whether measuring the cervix to guide treatment is necessary for women without other risk factors.

Table 17

Research recommendation rationale.

Table 18

Research recommendation modified PICO table.

3. At what gestation should treatment with prophylactic vaginal progesterone for the prevention of preterm birth be started and stopped?

Why this is important

Table 19

Research recommendation rationale.

Table 20

Research recommendation modified PICO table.

FINAL

This evidence review was developed by the National Guideline Alliance hosted by the Royal College of Obstetricians and Gynaecologists

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK552302PMID: 31913586

Table 1Summary of the protocol (PICO table)

Population	Pregnant women considered to be at risk of preterm labour and birth (<37⁺⁰ weeks’ gestation) because they have any of the following: a history of spontaneous preterm birth a history of preterm pre-labour rupture of membranes (in a previous pregnancy) a history of mid-trimester loss mid-trimester bleeding a history of cervical trauma a short cervix that has been identified on scan and/or bulging membranes in the current pregnancy a positive fetal fibronectin test
Intervention	Vaginal progesterone Oral progesterone
Comparison	One intervention compared to another Placebo No treatment
Outcome	Critical outcomes: Preterm birth <34⁺⁰ weeks’ Stillbirth Infant mortality prior to discharge Important outcomes: Gestational age at birth Early onset neonatal sepsis (onset up to 72 hours) Maternal satisfaction/HRQoL Neurodevelopmental outcome at ≥ 18 months

: HRQoL: health-related quality of life

Table 2Summary of included studies

Study	Participants	Intervention	Control	Outcomes
Ashoush 2017 RCT Egypt	N=187 women with history of spontaneous preterm birth	Oral progesterone (100 mg every 6 hours) Treatment started between 14 and 18 weeks’ gestational age	Placebo	Infant mortality Gestational age at birth
Azargoon 2016 RCT Iran	N=100 women with a history of preterm birth (52%) or previous history of preterm birth and short cervix (≤28 mm) (27%)	Vaginal progesterone (400 mg/day) Treatment started between 16 and 22 weeks’ gestational age	Placebo	Preterm birth <34 weeks’ Infant mortality Gestational age at birth
Crowther 2017 RCT Australia, New Zealand, Canada	N=799 women with history of spontaneous preterm birth	Vaginal progesterone (100mg/day) Treatment started at 20 weeks’ gestational age, or from randomisation (if this occurred after 20 weeks)	Placebo	Stillbirth Infant mortality Early neonatal sepsis Health-related quality of life
Dodd 2013 Cochrane systematic review Iran, Brazil, US, India	K=9 Akbari 2009 Cetingoz 2011 da Fonseca 2003 Fonseca 2007 Glover 2011 Hassan 2011 Majhi 2009 O´Brien 2007 Rai 2009 N=1892 women with a history of spontaneous preterm birth or short cervix on ultrasound scan	Vaginal progesterone (90 to 200 mg): Akbari 2009 Cetingoz 2011 da Fonseca 2003 Fonseca 2007 Hassan 2011 Majhi 2009 O´Brien 2007 Oral progesterone (100 to 200 mg): Glover 2011 Rai 2009 Treatment start week ranged between 16 and 24 weeks’ gestational age	Placebo	Preterm birth <34 weeks’ Stillbirth Infant mortality Gestational age at birth Neonatal sepsis
Norman 2018 RCT UK	N=1225 women with risk factors for preterm birth (including previous preterm birth, cervical length ≤25mm, second trimester loss, preterm premature rupture of the membranes or history of cervical procedure to treat abnormal smears)	Vaginal progesterone (200 mg/day) Treatment started between 22 and 24 weeks’ gestational age	Placebo	Preterm birth <34 weeks’ Stillbirth Infant mortality Gestational age at birth Health-related quality of life Bayley-III cognitive composite score Moderate or severe neuro-developmental impairment Visual impairment Hearing impairment
Romero 2018 ^a IPD meta-analysis UK, USA, Turkey	K= 5 Cetingoz 2011 Fonseca 2007 Hassan 2011 Norman 2016 O’Brien 2007 N=974 with a short cervix (≤25 mm)	Vaginal progesterone (90 to 200 mg/day) Treatment start week ranged between 18 and 24 weeks’ gestational age	Placebo	Preterm birth <34+0 weeks’ Stillbirth Infant mortality Gestational age at birth Proven neonatal sepsis Health-related quality of life Bayley-III cognitive composite score Moderate or severe neuro-developmental impairment Visual or hearing impairment
van Os 2015 RCT The Netherlands	N=80 women with a short cervix (≤30 mm)	Vaginal progesterone (200 mg) Treatment started at 22 weeks’ gestational age	Placebo	Preterm birth <34 weeks’ Infant mortality Neonatal sepsis

a: Romero 2018 contacted the principal investigators of the eligible trials. Data included in the IPD meta-analysis may have not been reported in the main trials.

: mg: milligrams; mm: millimetres; RCT: randomised controlled trial; IPD: individual patient data

Table 3Review protocol for clinical effectiveness of prophylactic progesterone in preventing preterm labour

Field (based on PRISMA-P)	Content
Key area in the scope	Prophylactic use of progesterone for women considered to be at risk of preterm labour and birth
Actual review question	What is the clinical effectiveness of prophylactic progesterone (vaginal or oral) in preventing preterm labour in pregnant women considered to be at risk of preterm labour and birth?
Type of review question	Intervention
Objective of the review	To establish if progesterone is effective in preventing preterm labour when given antenatally, and what is the most clinically effective type of progesterone (or has fewer/less severe adverse effects).
Eligibility criteria – population/disease/condition/issue/domain	Pregnant women considered to be at risk of preterm labour and birth (<37+0 weeks gestation) because they have any of the following: a history of spontaneous preterm birth a history of preterm pre-labour rupture of membranes (in a previous pregnancy) a history of mid-trimester loss mid-trimester bleeding a history of cervical trauma (including surgery – for example, previous cone biopsy [cold knife or laser], large loop excision of the transformation zone [LLETZ – any number] and radical diathermy). a short cervix that has been identified on scan and/or bulging membranes in the current pregnancy a positive fetal fibronectin test
Eligibility criteria – intervention(s)/exposure(s)/prognostic factor(s)	vaginal progesterone oral progesterone
Eligibility criteria – comparator(s)/control or reference (gold) standard	one intervention compared to another placebo no treatment
Outcomes and prioritisation	Critical: Preterm birth <34+0 weeks Stillbirth Infant mortality prior to discharge (includes neonatal mortality and additional mortality post 28 days, but prior to discharge) Important: Gestational age at birth Early onset neonatal sepsis (onset up to 72 hours) Maternal satisfaction/HRQOL Neurodevelopmental outcome at >/= 18 months
Eligibility criteria – study design	Only published full text papers Systematic reviews of RCTs RCTs
Other exclusion criteria	Women in actual preterm labour (as opposed to women at high risk for preterm labour) Multiple pregnancy Women with ruptured membranes (in the current pregnancy)
Proposed stratified, sensitivity/sub-group analysis, or meta-regression	Stratified analysis will be conducted for the following groups: a history of spontaneous preterm birth a history of preterm pre-labour rupture of membranes a history of mid-trimester loss mid-trimester bleeding a history of cervical trauma (including surgery) a short cervix that has been identified on scan and/or bulging membranes in the current pregnancy ≤25 mm ≤15 mm a positive fetal fibronectin test The following groups will be considered for subgroup analysis: gestational age groups (treatment commenced at <20 weeks, treatment commenced at ≥20 weeks)
Selection process – duplicate screening/selection/analysis	Duplicate screening/selection/analysis will not be undertaken for this review as this question was not prioritised for it. Included and excluded studies will be cross checked with the committee and with published systematic reviews when available.
Data management (software)	If pairwise meta-analyses are undertaken, they will be performed using Cochrane Review Manager (RevMan5). GRADE will be used to assess the quality of evidence for each outcome. STAR will be used for bibliographies/citations and study sifting, data extraction and quality assessment/critical appraisal
Information sources – databases and dates	Sources to be searched: Medline, Medline In-Process, CCTR, CDSR, Embase. Limits (e.g. date, study design): All study designs will be included. Standard animal/non-English language filters will be applied. the search date will be limited to 2015 onwards . No supplementary search techniques will be used. See appendix B for full strategies. Key papers: Norman JE et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. The Lancet. 2016 May 27;387(10033):2106–16. [PMC free article: PMC5406617] [PubMed: 26921136] Health Technol Assess. 2018 Jun;22(35):1–304. doi: 10.3310/hta22350. Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomised double-blind placebo-controlled trial (OPPTIMUM). Norman JE et al. [PMC free article: PMC6036405] [PubMed: 29945711] [CrossRef] PLoS Med. 2017 Sep 26;14(9):e1002390. doi: 10.1371/journal.pmed.1002390. eCollection 2017 Sep.Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial. Crowther CA, Ashwood P, McPhee AJ, Flenady V, Tran T, Dodd JM, Robinson JS; PROGRESS Study Group. [PMC free article: PMC5614421] [PubMed: 28949973] [CrossRef] Am J Obstet Gynecol. 2018 Feb;218(2):161–180. doi: 10.1016/j.ajog.2017.11.576. Epub 2017 Nov 17. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Romero R [PMC free article: PMC5987201] [PubMed: 29157866] [CrossRef] JAMA. 2017 Dec 19;318(23):2317–2324. doi: 10.1001/jama.2017.18956.Effect of Cervical Pessary on Spontaneous Preterm Birth in Women With Singleton Pregnancies and Short Cervical Length: A Randomized Clinical Trial.Saccone G [PMC free article: PMC5820698] [PubMed: 29260226] [CrossRef] Acta Obstet Gynecol Scand. 2017 Dec;96(12):1460–1466. doi: 10.1111/aogs.13236. Epub 2017 Oct 19. The value of oral micronized progesterone in the prevention of recurrent spontaneous preterm birth: a randomized controlled trial. Ashoush S [PubMed: 28949010] [CrossRef] Obstet Gynecol. 2017 Jul;130(1):64–70. doi: 10.1097/AOG.0000000000002065.Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial. Facchinetti F [PubMed: 28594783] [CrossRef] Cervical Pessary Compared With Vaginal Progesterone for Preventing Early Preterm Birth: A Randomized Controlled Trial. Cruz-Melguizo S, San-Frutos L, Martínez-Payo C, Ruiz-Antorán B, Adiego-Burgos B, Campillos-Maza JM, García-González C, Martínez-Guisasola J, Pérez-Carbajo E, Teulón-González M, Avendaño-Solá C, Pérez-Medina T. Obstet Gynecol. 2018 Oct;132(4):907–915. [PubMed: 30204689] Syst Rev. 2017 Nov 28;6(1):235. doi: 10.1186/s13643-017-0600-x. Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol. Stewart LA1, Simmonds M2, Duley L3, Dietz KC2, Harden M2, Hodkinson A2, Llewellyn A2, Sharif S2, Walker R2, Wright K2; EPPPIC group. [PMC free article: PMC5706301] [PubMed: 29183399] [CrossRef]
Identify if an update	Yes. Relevant evidence included in the existing guideline that aligns with this protocol will also be included in the updated review.
Author contacts	Developer: National Guideline Alliance ku.gro.GOCR@seiriuqne-AGN
Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual
Search strategy – for one database	For details please see appendix B.
Data collection process – forms/duplicate	A standardised evidence table format will be used, and published as appendix D (clinical evidence tables) or H (economic evidence tables).
Data items – define all variables to be collected	For details please see evidence tables in appendix D (clinical evidence tables) or H (economic evidence tables).
Methods for assessing bias at outcome/study level	Appraisal of methodological quality: The methodological quality of each study will be assessed using an appropriate checklist: ROBIS for systematic reviews Cochrane risk of bias tool for randomised studies For details please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence will evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis	For details please see section 6.4 of Developing NICE guidelines: the manual
Methods for quantitative analysis – combining studies and exploring (in)consistency	The methods used are described in more detail in the Methods section of the 2015 Preterm labour and birth full guideline. Synthesis of data: Meta-analysis will be conducted where appropriate using Review Manager. Minimally important differences Any significant difference will be used as the MID for mortality outcomes. For the remaining outcomes, default values will be used of: 0.8 and 1.25 for dichotomous outcomes; 0.5 times SD for continuous outcomes, unless more appropriate values are identified by the guideline committee or in the literature. Double sifting, data extraction and methodological quality assessment: Sifting, data extraction, appraisal of methodological quality and GRADE assessment will be performed by the systematic reviewer. Quality control will be performed by the senior systematic reviewer. Dual quality assessment and data extraction will not be performed.
Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual.
Confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual
Rationale/context – what is known	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the guideline. The committee was convened by the National Guideline Alliance and chaired by Sarah Fishburn in line with section 3 of Developing NICE guidelines: the manual. Staff from the National Guideline Alliance undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the guideline in collaboration with the committee. For details please see the methods chapter of the full guideline (published in 2015).
Sources of funding/support	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Name of sponsor	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Roles of sponsor	NICE funds the National Guideline Alliance to develop guidelines for the NHS in England.
PROSPERO registration number	Not registered with PROSPERO

Table 4Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations

#	Searches
1	META-ANALYSIS/
2	META-ANALYSIS AS TOPIC/
3	(meta analy* or metanaly* or metaanaly*).ti,ab.
4	((systematic* or evidence) adj2 (review or overview*)).ti,ab.
5	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
6	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
7	(search* adj4 literature).ab.
8	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
9	cochrane.jw.
10	or/1-9
11	randomized controlled trial.pt.
12	controlled clinical trial.pt.
13	pragmatic clinical trial.pt.
14	randomi#ed.ab.
15	placebo.ab.
16	randomly.ab.
17	CLINICAL TRIALS AS TOPIC/
18	trial.ti.
19	or/11-18
20	or/10,19
21	exp OBSTETRIC LABOR, PREMATURE/
22	exp INFANT, PREMATURE/
23	exp INFANT, LOW BIRTH WEIGHT/
24	GESTATIONAL AGE/
25	(pre term or preterm or pre matur$ or prematur$ or pre#mie? or premie or premies or low birth weight? or low birthweight? or LBW? or VLBW?).ti,ab.
26	or/21-25
27	PROGESTINS/
28	exp PROGESTERONE/
29	PROGESTERONE CONGENERS/
30	GONADAL STEROID HORMONES/
31	GESTONORONE CAPROATE/
32	(progest$ or gestagen$ or gestonorone? or hydroxyprogest$ or alphahydroxyprogest$ or 17alphahydroxyprogest$ or 17 OHP? or 17OHP?).mp.
33	(crinone or clycogest or gestone or utrogestan).mp.
34	or/27-33
35	CHEMOPREVENTION/
36	pc.fs. [Prevention & Control]
37	(prevent$ or reduc$ or prophyla$ or chemoprophyla$ or chemoprevent$ or prolong$ or inhibit$).ti,ab.
38	PRENATAL CARE/
39	(antenatal$ or ante natal$ or prenatal$ or pre natal$).ti,ab.
40	or/35-39
41	26 and 34 and 40
42	limit 41 to english language
43	LETTER/
44	EDITORIAL/
45	NEWS/
46	exp HISTORICAL ARTICLE/
47	ANECDOTES AS TOPIC/
48	COMMENT/
49	CASE REPORT/
50	(letter or comment*).ti.
51	or/43-50
52	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
53	51 not 52
54	ANIMALS/ not HUMANS/
55	exp ANIMALS, LABORATORY/
56	exp ANIMAL EXPERIMENTATION/
57	exp MODELS, ANIMAL/
58	exp RODENTIA/
59	(rat or rats or mouse or mice).ti.
60	or/53-59
61	42 not 60
62	20 and 61
63	(2015$ or 2016$ or 2017$ or 2018$).ed,yr.
64	62 and 63

Table 5Databases: Embase; and Embase Classic

#	Searches
1	SYSTEMATIC REVIEW/
2	META-ANALYSIS/
3	(meta analy* or metanaly* or metaanaly*).ti,ab.
4	((systematic or evidence) adj2 (review* or overview*)).ti,ab.
5	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
6	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
7	(search* adj4 literature).ab.
8	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
9	((pool* or combined) adj2 (data or trials or studies or results)).ab.
10	cochrane.jw.
11	or/1-10
12	random*.ti,ab.
13	factorial*.ti,ab.
14	(crossover* or cross over*).ti,ab.
15	((doubl* or singl) adj blind).ti,ab.
16	(assign* or allocat* or volunteer* or placebo*).ti,ab.
17	CROSSOVER PROCEDURE/
18	SINGLE BLIND PROCEDURE/
19	RANDOMIZED CONTROLLED TRIAL/
20	DOUBLE BLIND PROCEDURE/
21	or/12-20
22	11 or 21
23	PREMATURE LABOR/
24	PREMATURITY/
25	exp LOW BIRTH WEIGHT/
26	GESTATIONAL AGE/
27	(pre term or preterm or pre matur$ or prematur$ or pre#mie? or premie or premies or low birth weight? or low birthweight? or LBW? or VLBW?).ti,ab.
28	or/23-27
29	exp GESTAGEN/
30	PROGESTERONE/
31	exp PROGESTERONE DERIVATIVE/
32	SEX HORMONE/
33	GESTONORONE CAPROATE/
34	(progest$ or gestagen$ or gestonorone? or hydroxyprogest$ or alphahydroxyprogest$ or 17alphahydroxyprogest$ or 17 OHP? or 17OHP?).mp.
35	(crinone or clycogest or gestone or utrogestan).mp.
36	or/29-35
37	CHEMOPROPHYLAXIS/
38	pc.fs. [Prevention & Control]
39	(prevent$ or reduc$ or prophyla$ or chemoprophyla$ or chemoprevent$ or prolong$ or inhibit$).ti,ab.
40	PRENATAL CARE/
41	(antenatal$ or ante natal$ or prenatal$ or pre natal$).ti,ab.
42	or/37-41
43	28 and 36 and 42
44	limit 43 to english language
45	letter.pt. or LETTER/
46	note.pt.
47	editorial.pt.
48	CASE REPORT/ or CASE STUDY/
49	(letter or comment*).ti.
50	or/45-49
51	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
52	50 not 51
53	ANIMAL/ not HUMAN/
54	NONHUMAN/
55	exp ANIMAL EXPERIMENT/
56	exp EXPERIMENTAL ANIMAL/
57	ANIMAL MODEL/
58	exp RODENT/
59	(rat or rats or mouse or mice).ti.
60	or/52-59
61	44 not 60
62	22 and 61
63	(2015$ or 2016$ or 2017$ or 2018$).dd,yr.
64	62 and 63

Table 6Databases: Cochrane Central Register of Controlled Trials; and Cochrane Database of Systematic Reviews

#	Searches
#1	MeSH descriptor: [OBSTETRIC LABOR, PREMATURE] explode all trees
#2	MeSH descriptor: [INFANT, PREMATURE] explode all trees
#3	MeSH descriptor: [INFANT, LOW BIRTH WEIGHT] explode all trees
#4	MeSH descriptor: [GESTATIONAL AGE] this term only
#5	("pre term" or preterm or “pre matur” or prematur or premie or premies or “low birth weight” or “low birthweight” or LBW* or VLBW*):ti,ab
#6	#1 or #2 or #3 or #4 or #5
#7	MeSH descriptor: [PROGESTINS] this term only
#8	MeSH descriptor: [PROGESTERONE] explode all trees
#9	MeSH descriptor: [PROGESTERONE CONGENERS] this term only
#10	MeSH descriptor: [GONADAL STEROID HORMONES] this term only
#11	MeSH descriptor: [GESTONORONE CAPROATE] this term only
#12	(progest* or gestagen* or gestonorone* or hydroxyprogest* or alphahydroxyprogest* or 17alphahydroxyprogest* or “17 OHP” or 17OHP):ti,ab
#13	#7 or #8 or #9 or #10 or #11 or #12
#14	MeSH descriptor: [CHEMOPREVENTION] this term only
#15	[mh /PC]
#16	(prevent* or reduc* or prophyla* or chemoprophyla* or chemoprevent* or prolong* or inhibit*):ti,ab
#17	MeSH descriptor: [PRENATAL CARE] this term only
#18	(antenatal* or “ante natal” or prenatal or “pre natal*”):ti,ab
#19	#14 or #15 or #16 or #17 or #18
#20	#6 and #13 and #19 with Publication Year from 2015 to 2018, in Trials
#21	#6 and #13 and #19 with Cochrane Library publication date Between Jan 2015 and Dec 2018, in Cochrane Reviews

Table 7Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations

#	Searches
1	ECONOMICS/
2	VALUE OF LIFE/
3	exp “COSTS AND COST ANALYSIS”/
4	exp ECONOMICS, HOSPITAL/
5	exp ECONOMICS, MEDICAL/
6	exp RESOURCE ALLOCATION/
7	ECONOMICS, NURSING/
8	ECONOMICS, PHARMACEUTICAL/
9	exp “FEES AND CHARGES”/
10	exp BUDGETS/
11	budget*.ti,ab.
12	cost*.ti,ab.
13	(economic* or pharmaco?economic*).ti,ab.
14	(price* or pricing*).ti,ab.
15	(financ* or fee or fees or expenditure* or saving*).ti,ab.
16	(value adj2 (money or monetary)).ti,ab.
17	resourc* allocat*.ti,ab.
18	(fund or funds or funding* or funded).ti,ab.
19	(ration or rations or rationing* or rationed).ti,ab.
20	ec.fs.
21	or/1-20
22	exp OBSTETRIC LABOR, PREMATURE/
23	exp INFANT, PREMATURE/
24	exp INFANT, LOW BIRTH WEIGHT/
25	GESTATIONAL AGE/
26	(pre term or preterm or pre matur$ or prematur$ or pre#mie? or premie or premies or low birth weight? or low birthweight? or LBW? or VLBW?).ti,ab.
27	or/22-26
28	PROGESTINS/
29	exp PROGESTERONE/
30	PROGESTERONE CONGENERS/
31	GONADAL STEROID HORMONES/
32	GESTONORONE CAPROATE/
33	(progest$ or gestagen$ or gestonorone? or hydroxyprogest$ or alphahydroxyprogest$ or 17alphahydroxyprogest$ or 17 OHP? or 17OHP?).mp.
34	(crinone or clycogest or gestone or utrogestan).mp.
35	or/28-34
36	CHEMOPREVENTION/
37	pc.fs. [Prevention & Control]
38	(prevent$ or reduc$ or prophyla$ or chemoprophyla$ or chemoprevent$ or prolong$ or inhibit$).ti,ab.
39	PRENATAL CARE/
40	(antenatal$ or ante natal$ or prenatal$ or pre natal$).ti,ab.
41	or/36-40
42	27 and 35 and 41
43	limit 42 to english language
44	LETTER/
45	EDITORIAL/
46	NEWS/
47	exp HISTORICAL ARTICLE/
48	ANECDOTES AS TOPIC/
49	COMMENT/
50	CASE REPORT/
51	(letter or comment*).ti.
52	or/44-51
53	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
54	52 not 53
55	ANIMALS/ not HUMANS/
56	exp ANIMALS, LABORATORY/
57	exp ANIMAL EXPERIMENTATION/
58	exp MODELS, ANIMAL/
59	exp RODENTIA/
60	(rat or rats or mouse or mice).ti.
61	or/54-60
62	43 not 61
63	21 and 62
64	(2015$ or 2016$ or 2017$ or 2018$).ed,yr.
65	63 and 64

Table 8Databases: Embase; and Embase Classic

#	Searches
1	HEALTH ECONOMICS/
2	exp ECONOMIC EVALUATION/
3	exp HEALTH CARE COST/
4	exp FEE/
5	BUDGET/
6	FUNDING/
7	RESOURCE ALLOCATION/
8	budget*.ti,ab.
9	cost*.ti,ab.
10	(economic* or pharmaco?economic*).ti,ab.
11	(price* or pricing*).ti,ab.
12	(financ* or fee or fees or expenditure* or saving*).ti,ab.
13	(value adj2 (money or monetary)).ti,ab.
14	resourc* allocat*.ti,ab.
15	(fund or funds or funding* or funded).ti,ab.
16	(ration or rations or rationing* or rationed).ti,ab.
17	or/1-16
18	PREMATURE LABOR/
19	PREMATURITY/
20	exp LOW BIRTH WEIGHT/
21	GESTATIONAL AGE/
22	(pre term or preterm or pre matur$ or prematur$ or pre#mie? or premie or premies or low birth weight? or low birthweight? or LBW? or VLBW?).ti,ab.
23	or/18-22
24	exp GESTAGEN/
25	PROGESTERONE/
26	exp PROGESTERONE DERIVATIVE/
27	SEX HORMONE/
28	GESTONORONE CAPROATE/
29	(progest$ or gestagen$ or gestonorone? or hydroxyprogest$ or alphahydroxyprogest$ or 17alphahydroxyprogest$ or 17 OHP? or 17OHP?).mp.
30	(crinone or clycogest or gestone or utrogestan).mp.
31	or/24-30
32	CHEMOPROPHYLAXIS/
33	pc.fs. [Prevention & Control]
34	(prevent$ or reduc$ or prophyla$ or chemoprophyla$ or chemoprevent$ or prolong$ or inhibit$).ti,ab.
35	PRENATAL CARE/
36	(antenatal$ or ante natal$ or prenatal$ or pre natal$).ti,ab.
37	or/32-36
38	23 and 31 and 37
39	limit 38 to english language
40	letter.pt. or LETTER/
41	note.pt.
42	editorial.pt.
43	CASE REPORT/ or CASE STUDY/
44	(letter or comment*).ti.
45	or/40-44
46	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
47	45 not 46
48	ANIMAL/ not HUMAN/
49	NONHUMAN/
50	exp ANIMAL EXPERIMENT/
51	exp EXPERIMENTAL ANIMAL/
52	ANIMAL MODEL/
53	exp RODENT/
54	(rat or rats or mouse or mice).ti.
55	or/47-54
56	39 not 55
57	17 and 56
58	(2015$ or 2016$ or 2017$ or 2018$).dd,yr.
59	57 and 58

Table 9Database: Cochrane Central Register of Controlled Trials

#	Searches
#1	MeSH descriptor: [ECONOMICS] this term only
#2	MeSH descriptor: [VALUE OF LIFE] this term only
#3	MeSH descriptor: [COSTS AND COST ANALYSIS] explode all trees
#4	MeSH descriptor: [ECONOMICS, HOSPITAL] explode all trees
#5	MeSH descriptor: [ECONOMICS, MEDICAL] explode all trees
#6	MeSH descriptor: [RESOURCE ALLOCATION] explode all trees
#7	MeSH descriptor: [ECONOMICS, NURSING] this term only
#8	MeSH descriptor: [ECONOMICS, PHARMACEUTICAL] this term only
#9	MeSH descriptor: [FEES AND CHARGES] explode all trees
#10	MeSH descriptor: [BUDGETS] explode all trees
#11	budget*:ti,ab
#12	cost*:ti,ab
#13	(economic* or pharmaco?economic*):ti,ab
#14	(price* or pricing*):ti,ab
#15	(financ* or fee or fees or expenditure* or saving*):ti,ab
#16	(value near/2 (money or monetary)):ti,ab
#17	resourc* allocat*:ti,ab
#18	(fund or funds or funding* or funded):ti,ab
#19	(ration or rations or rationing* or rationed) .ti,ab.
#20	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19
#21	MeSH descriptor: [OBSTETRIC LABOR, PREMATURE] explode all trees
#22	MeSH descriptor: [INFANT, PREMATURE] explode all trees
#23	MeSH descriptor: [INFANT, LOW BIRTH WEIGHT] explode all trees
#24	MeSH descriptor: [GESTATIONAL AGE] this term only
#25	(“pre term” or preterm or “pre matur” or prematur or premie or premies or “low birth weight” or “low birthweight” or LBW* or VLBW*):ti,ab
#26	#21 or #22 or #23 or #24 or #25
#27	MeSH descriptor: [PROGESTINS] this term only
#28	MeSH descriptor: [PROGESTERONE] explode all trees
#29	MeSH descriptor: [PROGESTERONE CONGENERS] this term only
#30	MeSH descriptor: [GONADAL STEROID HORMONES] this term only
#31	MeSH descriptor: [GESTONORONE CAPROATE] this term only
#32	(progest* or gestagen* or gestonorone* or hydroxyprogest* or alphahydroxyprogest* or 17alphahydroxyprogest* or “17 OHP” or 17OHP):ti,ab
#33	#27 or #28 or #29 or #30 or #31 or #32
#34	MeSH descriptor: [CHEMOPREVENTION] this term only
#35	[mh /PC]
#36	(prevent* or reduc* or prophyla* or chemoprophyla* or chemoprevent* or prolong* or inhibit*):ti,ab
#37	MeSH descriptor: [PRENATAL CARE] this term only
#38	(antenatal* or “ante natal” or prenatal or “pre natal*”):ti,ab
#39	#34 or #35 or #36 or #37 or #38
#40	#26 and #33 and #39
#41	#20 and #40 with Publication Year from 2015 to 2018, in Trials

Figure 1Flow diagram of clinical article selection for clinical effectiveness of prophylactic progesterone in preventing preterm labour

Figure 1Preterm birth <34+0 weeks

Figure 2Stillbirth

Figure 3Infant mortality

Figure 4Gestational age at birth (mean weeks)

Figure 5Neonatal sepsis

Figure 6Neonatal sepsis; women with a short cervix (<30 mm); treatment started ≥ 20 weeks gestational age

[This figure is presented separately from figure 5 because a random effects model was utilised due to high heterogeneity for this subgroup]

Figure 7Infant mortality

Figure 8Gestational age at birth (mean weeks)

Table 11Comparison 1. Vaginal progesterone versus placebo

Quality assessment							Number of patients		Effect		Quality	Importance
Number of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Vaginal progesterone	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Preterm birth <34+0 weeks - Overall estimate
8 (Akbari 2009, Azargoon 2016, Cetingoz 2011, da Fonseca 2003, Fonseca 2007, Majhi 2009, Norman 2018, van Os 2015)	Randomised trials	Serious¹	Serious²	No serious indirectness	No serious imprecision	None	141/1079 (13.1%)	222/1066 (20.8%)	RR 0.50 (0.33 to 0.75)	104 fewer per 1000 (from 52 fewer to 140 fewer)	LOW	CRITICAL
Preterm birth <34+0 weeks – Subgroup analysis: Women with a history of spontaneous preterm birth
5 (Akbari 2009, Azargoon 2016, Cetingo 2011, da Fonseca 2003, Majhi 2009)	Randomised trials	Serious³	No serious inconsistency	No serious indirectness	No serious imprecision	None	13/256 (5.1%)	52/251 (20.7%)	RR 0.27 (0.15 to 0.49)	151 fewer per 1000 (from 106 fewer to 176 fewer)	MODERATE	CRITICAL
Preterm birth <34+0 weeks - Subgroup analysis: Women with a short cervix (overall estimate, <30 mm)
3 (Azargoon 2016, Fonseca 2007, van Os 2015)	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	Serious⁵	None	31/178 (17.4%)	55/179 (30.7%)	RR 0.58 (0.40 to 0.86)	129 fewer per 1000 (from 43 fewer to 184 fewer)	LOW	CRITICAL
Preterm birth <34+0 weeks - Subgroup analysis: Women with a short cervix (≤25 mm)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Serious⁵	None	86/498 (17.3%)	126/476 (26.5%)	RR 0.65 (0.51 to 0.83)	93 fewer per 1000 (from 45 fewer to 130 fewer)	LOW	CRITICAL
Stillbirth - Overall estimate
5 (Crowther 2017, Fonseca 2007, Hassan 2011, Norman 2018, O’Brien 2007)	Randomised trials	Serious⁷	No serious inconsistency	No serious indirectness	Very serious⁸	None	23/1686 (1.4%)	23/1653 (1.4%)	RR 0.98 (0.55 to 1.73)	0 fewer per 1000 (from 6 fewer to 10 more)	VERY LOW	CRITICAL
Stillbirth - Subgroup analysis: Women with a history of spontaneous preterm birth
2 (Crowther 2017, O’Brien 2007)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁸	None	9/715 (1.3%)	9/695 (1.3%)	RR 0.97 (0.39 to 2.44)	0 fewer per 1000 (from 8 fewer to 19 more)	LOW	CRITICAL
Stillbirth - Subgroup analysis: Women with a short cervix (≤25 mm)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Very serious⁸	None	9/498 (1.8%)	8/476 (1.7%)	RR 1.08 (0.42 to 2.76)	1 more per 1000 (from 10 fewer to 30 more)	VERY LOW	CRITICAL
Infant mortality - Overall estimate
9 (Akbari 2009, Azargoon 2016, Catingoz 2011, Crowther 2017, Fonseca 2007, Hassan 2011, Norman 2018, O’Brien 2007, van Os 2015)	Randomised trials	Serious⁹	No serious inconsistency	No serious indirectness	No serious imprecision	None	22/1926 (1.1%)	63/1884 (3.3%)	RR 0.34 (0.21 to 0.55)	22 fewer per 1000 (from 15 fewer to 26 fewer)	MODERATE	CRITICAL
Infant mortality - Subgroup analysis: Women with a history of spontaneous preterm birth
3 (Akbari 2009, Crowther 2017, O’Brien 2007)	Randomised trials	Serious¹⁰	No serious inconsistency	No serious indirectness	Serious⁵	None	10/784 (1.3%)	19/767 (2.5%)	RR 0.53 (0.25 to 1.12)	12 fewer per 1000 (from 19 fewer to 3 more)	LOW	CRITICAL
Infant mortality - Subgroup analysis: Women with a short cervix (overall, <30 mm)
3 (Fonseca 2007, Hassan 2011, van Os 2015)	Randomised trials	Serious¹¹	No serious inconsistency	No serious indirectness	Serious⁵	None	6/412 (1.5%)	14/400 (3.5%)	RR 0.42 (0.16 to 1.08)	20 fewer per 1000 (from 29 fewer to 3 more)	LOW	CRITICAL
Infant mortality - Subgroup analysis: Women with a short cervix (≤25 mm)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Serious⁵	None	7/498 (1.4%)	15/476 (3.2%)	RR 0.45 (0.18 to 1.08)	17 fewer per 1000 (from 26 fewer to 3 more)	LOW	CRITICAL
Gestational age at birth, weeks - Overall estimate (Better indicated by higher values)
3 (Azargoon 2016, Norman 2018, O’Brien 2007)	Randomised trials	Serious¹²	Very serious¹³	No serious indirectness	No serious imprecision	None	959	949	-	MD 0.65 higher (0.38 lower to 1.69 higher)	VERY LOW	IMPORTANT
Gestational age at birth, weeks - Subgroup analysis: Women with a history of spontaneous preterm birth (Better indicated by higher values)
2 (Azargoon 2016, O’Brien 2007)	Randomised trials	Serious¹²	Very serious¹³	No serious indirectness	No serious imprecision	none	359	352	-	MD 1.35 higher (1.49 lower to 4.18 higher)	VERY LOW	CRITICAL
Gestational age at birth, weeks - Subgroup analysis: Women with a short cervix (≤25mm) (Better indicated by higher values)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	No serious imprecision	None	498	476	-	MD 0.74 higher (0.18 to 1.30 higher)	MODERATE	IMPORTANT
Neonatal sepsis - Overall estimate
6 (Akbari 2009, Crowther 2017, Fonseca 2007, Hassan 2011, Majhi 2009, van Os 2015)	Randomised trials	Serious¹⁴	No serious inconsistency	No serious indirectness	Serious⁵	None	10/933 (1.1%)	26/910 (2.9%)	RR 0.41 (0.21 to 0.82)	17 fewer per 1000 (from 5 fewer to 23 fewer)	LOW	IMPORTANT
Neonatal sepsis - Subgroup analysis: Women with a history of spontaneous preterm birth
3 (Akbari 2009, Crowther 2017, Majhi 2009)	Randomised trials	Serious¹⁵	No serious inconsistency	No serious indirectness	No serious imprecision	None	0/521 (0%)	9/510 (1.8%)	RR 0.14 (0.03 to 0.79)	15 fewer per 1000 (from 4 fewer to 17 fewer)	MODERATE	IMPORTANT
Neonatal sepsis - Subgroup analysis: Women with a short cervix (overall estimate, <30mm)
3 (Fonseca 207, Hassan 2011, van Os 2015)	Randomised trials	Serious¹¹	Serious²	No serious indirectness	Serious⁸	None	10/412 (2.4%)	17/400 (4.3%)	RR 0.58 (0.15 to 2.25)	18 fewer per 1000 (from 36 fewer to 53 more)	VERY LOW	IMPORTANT
Neonatal sepsis - Subgroup analysis: Women with a short cervix (≤25 mm)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Serious⁵	None	18/494 (3.6%)	28/470 (6%)	RR 0.61 (0.34 to 1.09)	23 fewer per 1000 (from 39 fewer to 5 more)	LOW	IMPORTANT
Health-related quality of life (measured with EuroQoL-5 Dimensions health utility scores) - Change between groups from baseline to birth (Better indicated by lower values)
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	191	199	-	MD 0.00 higher (0.04 lower to 0.04 higher)	HIGH	IMPORTANT
Health-related quality of life (measured with EuroQoL-5 Dimensions health utility scores) - Change between groups from baseline to 12 months (Better indicated by lower values)
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	279	274	-	MD 0.01 higher (0.03 lower to 0.04 higher)	HIGH	IMPORTANT
Health-related quality of life (measured with SF-36) [history of spontaneous PTB] - General health (Better indicated by higher values)
1 (Crowther 2017)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	398	389	-	MD 1.53 higher (0.96 lower to 4.02 higher)	HIGH	IMPORTANT
Health-related quality of life (measured with SF-36) [history of spontaneous PTB] - Social functioning (Better indicated by higher values)
1 (Crowther 2017)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	398	389	-	MD 3.8 lower (7.48 to 0.12 lower)	HIGH	IMPORTANT
Health-related quality of life (measured with SF-36) [history of spontaneous PTB] - Emotional role (Better indicated by higher values)
1 (Crowther 2017)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	398	389	-	MD 3.31 lower (7.91 lower to 1.29 higher)	HIGH	IMPORTANT
Health-related quality of life (measured with SF-36) [history of spontaneous PTB] - Mental health (Better indicated by higher values)
1 (Crowther 2017)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	398	389	-	MD 0.32 lower (2.7 lower to 2.06 higher)	HIGH	IMPORTANT
Bayley-III cognitive composite score (2 years follow-up) [overall estimate] (Better indicated by higher values)
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	410	423	-	MD 0.20 higher (1.82 lower to 2.22 higher)	HIGH	IMPORTANT
Bayley-III cognitive composite score ( 2 years follow-up) Subgroup analysis: women with short cervix ≤25 mm (Better indicated by higher values)
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	No serious imprecision	None	88	80	-	MD 2.2 lower (7.2 lower to 2.8 higher)	MODERATE	IMPORTANT
Moderate or severe neurodevelopmental impairment (2 years follow-up) [overall estimate]
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious⁵	None	47/379 (12.4%)	35/403 (8.7%)	RR 1.43 (0.94 to 2.16)	37 more per 1000 (from 5 fewer to 101 more)	MODERATE	IMPORTANT
Moderate or severe neurodevelopmental impairment (2 years follow-up) Subgroup analysis: Women with short cervix ≤25 mm
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Very serious⁸	None	10/81 (12.3%)	7/77 (9.1%)	RR 1.36 (0.54 to 3.39)	33 more per 1000 (from 42 fewer to 217 more)	VERY LOW	IMPORTANT
Hearing impairment (2 years follow-up) [overall estimate]
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁸	None	1/466 (0.21%)	2/465 (0.43%)	RR 0.50 (0.05 to 5.48)	2 fewer per 1000 (from 4 fewer to 19 more)	LOW	IMPORTANT
Visual impairment (2 years follow-up) [overall estimate]
1 (Norman 2018)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Very serious⁸	None	0/447 (0%)	4/465 (0.86%)	RR 0.12 (0.01 to 2.15)	8 fewer per 1000 (from 9 fewer to 10 more)	LOW	IMPORTANT
Visual or hearing impairment (2 years follow-up) [women with short cervix ≤25 mm]
1 (Romero 2018)	Randomised trials	Serious⁶	No serious inconsistency	No serious indirectness	Very serious⁸	None	0/100 (0%)	2/87 (2.3%)	RR 0.17 (0.01 to 3.58)	19 fewer per 1000 (from 23 fewer to 59 more)	VERY LOW	IMPORTANT

1: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in one study; unclear risk of blinding of participants and personnel in two studies; unclear risk of blinding of outcome assessors in four studies; unclear risk of incomplete outcome data in one study and unclear risk of other bias in two studies

2: The quality of the evidence was downgraded by one level as the I² was >50%

3: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in two studies; unclear risk of blinding of participants and personnel in two studies; unclear risk of blinding of outcome assessors in three studies; unclear risk of incomplete outcome data in one study; unclear risk of other bias in two studies

4: The quality of the evidence was downgraded by one level due to unclear risk of allocation concealment in two studies; unclear risk of blinding of participants and personnel in one study; unclear risk of blinding of outcome assessors in two studies and unclear risk of selective reporting in one study

5: The quality of the evidence was downgraded by one level as the 95% CI crossed 1 default MID threshold (0.8)

6: The quality of the evidence was downgraded by one level as the review authors did not provide a list of excluded studies justifying the reasons for exclusion, sources of funding of the studies were not provided and publication bias was not discussed in one study

7: The quality of the evidence was downgraded by one level due to unclear risk of allocation concealment in one study and high risk of other bias in one study

8: The quality of the evidence was downgraded by two levels as the 95% CI crossed 2 default MID thresholds (0.8 and 1.25)

9: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in four studies; unclear risk of blinding of outcome assessors in three studies; unclear risk of incomplete outcome data in one study; unclear risk of other bias in one study and unclear risk of selective reporting in one study

10: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in two studies; unclear risk of blinding of participants and personnel in one study; unclear risk of blinding of outcome assessors in one study; unclear risk of incomplete outcome data in one study; unclear risk of other bias in one study

11: The quality of the evidence was downgraded by one level due to unclear risk of allocation concealment in one study; unclear risk of blinding of outcome assessors in one study and unclear risk of selective reporting in one study

12: The quality of the evidence was downgraded by one level due to unclear risk of allocation concealment in one study and unclear risk of blinding of outcome assessors in one study

13: The quality of the evidence was downgraded by two levels as the I² was >70%

14: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in three studies; unclear risk of blinding of participants and personnel in one study; unclear risk of blinding of outcome assessors in two studies; unclear risk of incomplete outcome data in one study; unclear risk of selective reporting in one study and unclear risk of other bias in two studies

15: The quality of the evidence was downgraded by one level due to unclear risk of random sequence generation in one study; unclear risk of allocation concealment in two studies; unclear risk of blinding of participants and personnel in two studies; unclear risk of blinding of outcome assessors in one study; unclear risk of incomplete outcome data in one study; unclear risk of other bias in one study

Table 12Comparison 2. Oral progesterone versus placebo

Quality assessment							Number of patients		Effect		Quality	Importance
Number of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Oral progesterone	Placebo	Relative (95% CI)	Absolute	Quality	Importance
Preterm birth <34+0 weeks [history of spontaneous PTB]
1 (Rai 2009)	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious¹	None	22/74 (29.7%)	37/74 (50%)	RR 0.59 (0.39 to 0.90)	205 fewer per 1000 (from 50 fewer to 305 fewer)	MODERATE	CRITICAL
Infant mortality [history of spontaneous PTB]
2 (Ashoush 2017, Rai 2009)	Randomised trials	Serious²	No serious inconsistency	No serious indirectness	No serious imprecision	None	10/170 (5.9%)	30/165 (18.2%)	RR 0.32 (0.16 to 0.63)	124 fewer per 1000 (from 67 fewer to 153 fewer)	MODERATE	CRITICAL
Gestational age at birth, weeks [history of spontaneous PTB] (Better indicated by higher values)
2 (Ashoush 2017, Glover 2011)	Randomised trials	Serious³	No serious inconsistency	No serious indirectness	No serious imprecision	None	115	105	-	MD 1.43 higher (0.70 to 2.17 higher)	MODERATE	IMPORTANT

1: The quality of the evidence was downgraded by one level as the 95% CI crossed 1 default MID threshold (0.8)

2: The quality of the evidence was downgraded by one level due to unclear risk of blinding of outcome assessors in two studies

3: The quality of the evidence was downgrade by one level due to unclear risk of blinding outcome assessors and unclear risk of selective reporting in one study

Figure 9Economic evidence study selection

Table 13Clinical studies

Study	Reason for Exclusion
Ahn, K. H., Bae, N. Y., Hong, S. C., Lee, J. S., Lee, E. H., Jee, H. J., Cho, G. J., Oh, M. J., Kim, H. J., The safety of progestogen in the prevention of preterm birth: meta-analysis of neonatal mortality, Journal of Perinatal Medicine, 45, 11–20, 2017 [PubMed: 27124668]	This systematic review also considered studies including women with multiple pregnancies or where progesterone was administered intramuscularly. Relevant studies have been assessed and included as appropriate
Areeruk, W., Phupong, V., A randomized, double blinded, placebo controlled trial of oral dydrogesterone supplementation in the management of preterm labor, Scientific reports, 6, 20638, 2016 [PMC free article: PMC4816161] [PubMed: 26856618]	Progesterone was used as tocolytic - acute treatment
Arya, R., Randomized trial of natural micronized progesterone in prevention of preterm birth in women at high risk, BJOG: an international journal of obstetrics and gynaecology. Conference: 2018 world congress of the royal college of obstretriscians and gynaecologists, RCOG 2018. Singapore, 125, 67, 2018	Conference abstract
Barinov, Sergey V., Shamina, Inna V., Di Renzo, Gian Carlo, Lazareva, Oksana V., Tirskaya, Yuliya I., Medjannikova, Irina V., Ledovskikh, Inna O., Klementyeva, Lyudmila L., Dudkova, Galina V., The role of cervical pessary and progesterone therapy in the phenomenon of placenta previa migration, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 1–11, 2018 [PubMed: 30081730]	Mixed population. Most women (90%) were included for other risk factors than the ones stated in the protocol
Barinov, Sergey V., Shamina, Irina V., Lazareva, Oksana V., Tirskaya, Yuliya I., Ralko, Vyacheslav V., Shkabarnya, Lyudmila L., Dikke, Galina B., Kochev, Dmitry M., Klementyeva, Lyudmila L., Comparative assessment of arabin pessary, cervical cerclage and medical management for preterm birth prevention in high-risk pregnancies, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 30, 1841–1846, 2017 [PubMed: 27550418]	No relevant comparators (cerclage/ pessary with no progesterone)
Chaman-Ara, K., Bahrami, M. A., Bahrami, E., Bahrami, S., Bahrami, M. N., Moosazadeh, M., Barati, O., Efficacy of progesterone therapy in the prevention of preterm labor in women with mixed risk-factors: A systematic review and meta-analysis of randomized clinical trials, Erciyes Tip Dergisi, 38, 48–52, 2016	This systematic review included 3 studies; 2 of which are not relevant due to population and intervention characteristics (Dudas,Johnson). The remaining study (Cetingoz) has already been included in this review
Choi, Suk-Joo, Use of progesterone supplement therapy for prevention of preterm birth: review of literatures, Obstetrics & gynecology science, 60, 405–420, 2017 [PMC free article: PMC5621069] [PubMed: 28989916]	This systematic review has also considered studies including women with multiple pregnancies or where progesterone was administered intramuscularly. Relevant studies have been assessed and included as appropriate
Choudhary, Manju, Suneja, Amita, Vaid, Neelam B., Guleria, Kiran, Faridi, M. M. A., Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 126, 60–3, 2014 [PubMed: 24807871]	Progesterone is being used as tocolytic - acute treatment
Conde-Agudelo, Agustin, Romero, Roberto, Da Fonseca, Eduardo, O’Brien, John M., Cetingoz, Elcin, Creasy, George W., Hassan, Sonia S., Erez, Offer, Pacora, Percy, Nicolaides, Kypros H., Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis, American Journal of Obstetrics and Gynecology, 219, 10–25, 2018 [PMC free article: PMC6449041] [PubMed: 29630885]	Cervical cerclage comparison is not relevant
Coomarasamy, Arri, Williams, Helen, Truchanowicz, Ewa, Seed, Paul T., Small, Rachel, Quenby, Siobhan, Gupta, Pratima, Dawood, Feroza, Koot, Yvonne E. M., Bender Atik, Ruth, Bloemenkamp, Kitty W. M., Brady, Rebecca, Briley, Annette L., Cavallaro, Rebecca, Cheong, Ying C., Chu, Justin J., Eapen, Abey, Ewies, Ayman, Hoek, Annemieke, Kaaijk, Eugenie M., Koks, Carolien A. M., Li, Tin-Chiu, MacLean, Marjory, Mol, Ben W., Moore, Judith, Ross, Jackie A., Sharpe, Lisa, Stewart, Jane, Vaithilingam, Nirmala, Farquharson, Roy G., Kilby, Mark D., Khalaf, Yacoub, Goddijn, Mariette, Regan, Lesley, Rai, Rajendra, A Randomized Trial of Progesterone in Women with Recurrent Miscarriages, The New England journal of medicine, 373, 2141–8, 2015 [PubMed: 26605928]	Women with recurrent miscarriages, not pre term birth
Cruz-Melguizo, Sara, San-Frutos, Luis, Martinez-Payo, Cristina, Ruiz-Antoran, Belen, Adiego-Burgos, Begona, Campillos-Maza, Jose Manuel, Garcia-Gonzalez, Celso, Martinez-Guisasola, Javier, Perez-Carbajo, Esther, Teulon-Gonzalez, Maria, Avendano-Sola, Cristina, Perez-Medina, Tirso, Cervical Pessary Compared With Vaginal Progesterone for Preventing Early Preterm Birth: A Randomized Controlled Trial, Obstetrics and Gynecology, 132, 907–915, 2018 [PubMed: 30204689]	No relevant comparison (pessary without progesterone)
Dodd, J. M., Grivell, R. M., Obrien, C. M., Deussen, A. R., Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a singleton pregnancy, Cochrane Database of Systematic Reviews, 2017, CD012531, 2017 [PMC free article: PMC6485912] [PubMed: 29086920]	Protocol
Dugoff, L., Berghella, V., Sehdev, H., Mackeen, A. D., Goetzl, L., Ludmir, J., Prevention of preterm birth with pessary in singletons (PoPPS): randomized controlled trial, Ultrasound in obstetrics & gynecology, 51, 573–579, 2018 [PubMed: 28940481]	No relevant comparison (pessary without progesterone)
Eichelberger, Kacey Y., Manuck, Tracy A., Progesterone has no place in the prevention of preterm delivery: AGAINST: A call for a measured response to the OPPTIMUM trial, BJOG : an international journal of obstetrics and gynaecology, 123, 1511, 2016 [PubMed: 27440593]	Comment letter
Eke, Ahizechukwu C., Chalaan, Tina, Shukr, Ghadear, Eleje, George U., Okafor, Charles I., A systematic review and meta-analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 132, 11–6, 2016 [PMC free article: PMC9941008] [PubMed: 26489489]	No relevant studies have been included
Facchinetti, Fabio, Vergani, Patrizia, Di Tommaso, Mariarosaria, Marozio, Luca, Acaia, Barbara, Vicini, Roberto, Pignatti, Lucrezia, Locatelli, Anna, Spitaleri, Marina, Benedetto, Chiara, Zaina, Barbara, D’Amico, Roberto, Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial, Obstetrics and Gynecology, 130, 64–70, 2017 [PubMed: 28594783]	Women in the control group received progesterone IM
Garmi, G., Hakim, M., Zafran, N., Nachum, Z., Romano, S., Salim, R., The impact of progesterone on the risk of preterm birth among women with second trimester bleeding. A multicenter, randomized, double-blind, placebo controlled trial, American journal of obstetrics and gynecology. Conference: 38th annual meeting of the society for maternal-fetal medicine: the pregnancy meeting. United states, 218, S108, 2018	Abstract
Grabovac, M., Lewis-Mikhael, A. M., McDonald, S. D., Interventions to Try to Prevent Preterm Birth in Women With a History of Conization: A Systematic Review and Meta-analyses, Journal of Obstetrics and Gynaecology Canada, 2018 [PubMed: 30585167]	No relevant interventions
Hermans, F. J. R., Karolinski, A., Othenin-Girard, V., Bertolino, M. V., Schuit, E., Salgado, P., Hosli, I., Irion, O., Laterra, C., Mol, B. W. J., Martinez de Tejada, B., Population differences and the effect of vaginal progesterone on preterm birth in women with threatened preterm labor*, Journal of Maternal-Fetal and Neonatal Medicine, 29, 3223–3228, 2016 [PubMed: 26586448]	No relevant outcomes have been reported
Hermans, Frederik J. R., Schuit, Ewoud, Opmeer, Brent C., Oudijk, Martijn A., Bekker, Mireille, Woiski, Mallory, Bax, Caroline J., Sueters, Marieke, Scheepers, Hubertina C. J., Franssen, Maureen T. M., Pajkrt, Eva, Mol, Ben Willem J., Kok, Marjolein, Effectiveness of a cervical pessary for women who did not deliver 48 h after threatened preterm labor (Assessment of perinatal outcome after specific treatment in early labor: Apostel VI trial), BMC Pregnancy and Childbirth, 16, 154, 2016 [PMC free article: PMC4942883] [PubMed: 27405353]	Protocol
Hezelgrave, Natasha L., Watson, Helena A., Ridout, Alexandra, Diab, Falak, Seed, Paul T., Chin-Smith, Evonne, Tribe, Rachel M., Shennan, Andrew H., Rationale and design of SuPPoRT: a multi-centre randomised controlled trial to compare three treatments: cervical cerclage, cervical pessary and vaginal progesterone, for the prevention of preterm birth in women who develop a short cervix, BMC Pregnancy and Childbirth, 16, 358, 2016 [PMC free article: PMC5117554] [PubMed: 27871275]	Protocol
Hui, C. Y. Y., Siew, S. J. Y., Tan, T. C., Biochemical and clinical outcomes following the use of micronised progesterone and dydrogesterone for threatened miscarriage - A randomised controlled trial, BJOG: An International Journal of Obstetrics and Gynaecology, 122, 276, 2015	Conference abstract
Iwami, N., Hirayama, N., Kobayashi, Y., Kanaya, M., Yagi, A., Saito, T., Ozawa, J., Yamamoto, T., Watanabe, E., Moriwaka, O., Kamiya, H., New trial of dydrogesterone regimen as an effective oral alternative for suppression of premature luteinizing hormone surges during controlled ovarian stimulation of assisted reproductive therapy, Human Reproduction, 32, 2017	Conference abstract
Jarde, A., Lutsiv, O., Park, C. K., Beyene, J., Dodd, J. M., Barrett, J., Shah, P. S., Cook, J. L., Saito, S., Biringer, A. B., Sabatino, L., Giglia, L., Han, Z., Staub, K., Mundle, W., Chamberlain, J., McDonald, S. D., Effectiveness of progesterone, cerclage and pessary for preventing preterm birth in singleton pregnancies: a systematic review and network meta-analysis, BJOG: An International Journal of Obstetrics & Gynaecology, 124, 1176–1189, 2017 [PubMed: 28276151]	Intramuscular and oral progesterone were combined in the meta-analyses. The relevant studies have already been included in Dodd 2013
Lucovnik, Miha, Trojner Bregar, Andreja, Bombac, Lea, Gersak, Ksenija, Garfield, Robert E., Effects of vaginal progesterone for maintenance tocolysis on uterine electrical activity, The journal of obstetrics and gynaecology research, 44, 408–416, 2018 [PubMed: 29297950]	Progesterone used as tocolytic-acute treatment
Martinez de Tejada, B., Karolinski, A., Ocampo, M. C., Laterra, C., Hosli, I., Fernandez, D., Surbek, D., Huespe, M., Drack, G., Bunader, A., Rouillier, S., Lopez de Degani, G., Seidenstein, E., Prentl, E., Anton, J., Krahenmann, F., Nowacki, D., Poncelas, M., Nassif, J. C., Papera, R., Tuma, C., Espoile, R., Tiberio, O., Breccia, G., Messina, A., Peker, B., Schinner, E., Mol, B. W., Kanterewicz, L., Wainer, V., Boulvain, M., Othenin-Girard, V., Bertolino, M. V., Irion, O., P. trial group, Martinez de Tejada B, Irion O. Boulvain M. Tellenbach M. Othenin-Girard V. Vogele E. Azbar R. Hosli I. Raggi A. Birkenmaier A. Kann S. Surbek D. Scheibner K. Huguelet M. Amann E. Baumann M. Jakob E. Biedermann K. Hodel M. Drack G. Fischer T. Pfau K. Estermann K. Hohlfeld P. Gerber S. Rouiller-Cornu S. Capoccia Brugger R. Nessi A. Rodriguez-Maillot C. Pradervand P. A. Bodenmann P. Fornage S. Prentl E. Amann E. Krahenmann F. Zimmermann R. Karolinski A. Bertolino M. V. Ocampo M. C. Wainer V. Kanterewicz L. Rodriguez C. Colazo L. Laterra C. Ramirez Almanza S. Swistak E. Gonzalez Y. Fernandez D. Zalazar G. Rubino M. Sanchez B. Rivara A. Mercado C. Sagarna S. Huespe M. Luca R. Claus L. Castellano V. Domingo L. Castro C. Gil D. Rodriguez M. E. Bunader A. Capua N. E. Romano M. Longo M. E. Balbo E. Martinez Lozano S. Petros C. Lopez de Degani G. Coniglio M. Harris R. Leanga M. Martinez R. Felici F. de Bueno M. Reffino F. Castagnola J. Brarda P. Parra M. E. Montenegro R. Fernandez G. Schmadke G. Seidenstein E. Pontoriero R. Gonzalez C. Alduncin J. Anton J. Damiano M. Sanchez G. Rebottaro M. Altamira L. Garbarino V. Rebottaro C. Nowacki D. Ferrary M. Buttner C. Gonzalez P. Godoy Y. Poncelas M. Bertola E. Langdon L. Jimenez O. Mezzabota L. Nassif J. C. Becker C. A. Baier J. M. Grichener M. Trotti P. Papera R. Chaloupka M. Zarate M. Bogino L. Bertone E. Olmedo F. Barrionuevo M. Mariojouls N. Tuma C. Gregoris C. Espoile R. Muzio C. Nocetto C. Carozzi D. Pelaez V. De Moura C. Tiberio O. Sagastume M. Martinez L. Morales D. Penna J. Breccia G. Aguilera E. Werbicki E. Bover S. Alvarez T. Messina A. Stillo M. F. Joao M. Crema D. Wiliams L. Espada C. Gomariz V. Calo M. E. Peker B. Longhi D. Pisanelli M. L. Giglio L. Rodriguez J. Perez Petruzzelli R. Gores I. Schinner E. Morcillo M. V. Terenzani F. Izbizky G. Gimenez M. L. Meller C. Grasso M. Martinotti M. Scheller I. Marinelli J. Carrizo L. Baro S. Marasco N., Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial, BJOG : an international journal of obstetrics and gynaecology, 122, 80–91, 2015 [PubMed: 25209926]	No relevant population (women were in preterm labour)
Martinez de Tejada, Begona, Karolinski, Ariel, Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials, American Journal of Obstetrics and Gynecology, 213, 438–9, 2015 [PubMed: 26003056]	Comment letter
Medley, N., Poljak, B., Mammarella, S., Alfirevic, Z., Clinical guidelines for prevention and management of preterm birth: a systematic review, BJOG: An International Journal of Obstetrics & Gynaecology, 20, 20, 2018 [PubMed: 29460323]	Review of current clinical practice guidelines, no data was presented
Nicolaides, K. H., Syngelaki, A., Poon, L. C., Picciarelli, G., Tul, N., Zamprakou, A., Skyfta, E., Parra-Cordero, M., Palma-Dias, R., Calvo, J. R., A randomized trial of a cervical pessary to prevent preterm singleton birth, New England journal of medicine, 374, 1044–1052, 2016 [PubMed: 26981934]	Progesterone was provided to women with a short cervix, but the study was not designed to test its effectiveness as women in both treatment arms received it
Norman JE, Marlow N, Messow CM, Shennan A, Bennett PR, Thornton S, Robson SC, McConnachie A, Petrou S, Sebire NJ, Lavender T. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. The lancet. 2016 May 21;387(10033):2106–16. [PMC free article: PMC5406617] [PubMed: 26921136]	Relevant outcomes have been extracted under Norman 2018
Palacio, M., Cobo, T., Antolin, E., Ramirez, M., Cabrera, F., De Rosales, F. M., Bartha, J. L., Juan, M., Marti, A., Oros, D., Rodriguez, A., Scazzocchio, E., Olivares, J. M., Varea, S., Rios, J., Gratacos, E., Vaginal Progesterone as Maintenance Treatment after an Episode of Preterm Labour (PROMISE) Study: A Multicentre, Double-blind, Randomised, Placebo-Controlled Trial, Obstetrical and Gynecological Survey, 72, 151–153, 2017 [PubMed: 27028759]	Progesterone used as maintenance treatment
Palacio, M., Cobo, T., Antolin, E., Ramirez, M., Cabrera, F., Mozo de Rosales, F., Bartha, J. L., Juan, M., Marti, A., Oros, D., Rodriguez, A., Scazzocchio, E., Olivares, J. M., Varea, S., Rios, J., Gratacos, E., Trilla, A., Carralero, I., Mendez, F., Arnaiz, J. A., Ramos, N., Pejenaute, A., Garcia, D., Carne, X., Murphy, K. E., Crowther, C., Ohlsson, A., Torres, F., Vaginal progesterone as maintenance treatment after an episode of preterm labour (PROMISE) study: a multicentre, double-blind, randomised, placebo-controlled trial, BJOG: An International Journal of Obstetrics and Gynaecology, 123, 1990–1999, 2016 [PubMed: 27028759]	Progesterone used as maintenance treatment
Prior, M., Hibberd, R., Asemota, N., Thornton, J. G., Inadvertent P-hacking among trials and systematic reviews of the effect of progestogens in pregnancy? A systematic review and meta-analysis, BJOG: An International Journal of Obstetrics & GynaecologyBjog, 20, 20, 2017 [PubMed: 28318099]	The main aim of this study does not match with the main aim of this review
Romero, R., Nicolaides, K. H., Conde-Agudelo, A., O’Brien, J. M., Cetingoz, E., Da Fonseca, E., Creasy, G. W., Hassan, S. S., Vaginal progesterone decreases preterm birth<=34weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study, Ultrasound in Obstetrics & Gynecology, 48, 308–17, 2016 [PMC free article: PMC5053235] [PubMed: 27444208]	Updated by Romero 2018
Saccone, G., Maruotti, G. M., Giudicepietro, A., Martinelli, P., Effect of Cervical Pessary on Spontaneous Preterm Birth in Women with Singleton Pregnancies and Short Cervical Length: A Randomized Clinical Trial, Obstetrical and Gynecological Survey, 73, 267–268, 2018 [PMC free article: PMC5820698] [PubMed: 29260226]	Progesterone was provided to women with a short cervix, but the study was not designed to test its effectiveness as women in both treatment arms received it
Saccone, Gabriele, Schoen, Corina, Franasiak, Jason M., Scott, Richard T., Jr., Berghella, Vincenzo, Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials, Fertility and Sterility, 107, 430–438.e3, 2017 [PubMed: 27887710]	Women with recurrent miscarriages, not pre term birth
Stewart, L. A., Simmonds, M., Duley, L., Dietz, K. C., Harden, M., Hodkinson, A., Llewellyn, A., Sharif, S., Walker, R., Wright, K., Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: Protocol, Systematic Reviews, 6 (1) (no pagination), 2017 [PMC free article: PMC5706301] [PubMed: 29183399]	Protocol
Suhag, Anju, Saccone, Gabriele, Berghella, Vincenzo, Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials, American Journal of Obstetrics and Gynecology, 213, 479–87, 2015 [PubMed: 25797233]	Progesterone used as maintenance treatment
van Zijl, Maud D., Koullali, Bouchra, Naaktgeboren, Christiana A., Schuit, Ewoud, Bekedam, Dick J., Moll, Etelka, Oudijk, Martijn A., van Baal, Wilhelmina M., de Boer, Marjon A., Visser, Henricus, van Drongelen, Joris, van de Made, Flip W., Vollebregt, Karlijn C., Muller, Moira A., Bekker, Mireille N., Brons, Jozien T. J., Sueters, Marieke, Langenveld, Josje, Franssen, Maureen T., Schuitemaker, Nico W., van Beek, Erik, Scheepers, Hubertina C. J., de Boer, Karin, Tepe, Eveline M., Huisjes, Anjoke J. M., Hooker, Angelo B., Verheijen, Evelyn C. J., Papatsonis, Dimitri N., Mol, Ben Willem J., Kazemier, Brenda M., Pajkrt, Eva, Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial, BMC Pregnancy and Childbirth, 17, 284, 2017 [PMC free article: PMC5584011] [PubMed: 28870155]	Pessary does not contain progesterone
Van’t Hooft, J., Cuijpers, C., Schneeberger, C., Van Der Lee, J. H., Opmeer, B. C., Steenis, L., Liem, S., Van De Beek, C., Van Os, M., Van Der Ven, J., De Groot, C. J. M., Mol, B. W. J., Van Wassenaer-Leemhuis, A. G., Preventing preterm birth with progesterone in women with short cervical length, outcomes in children at 24 months of age, American Journal of Obstetrics and Gynecology, 216, S492, 2017	Abstract

Table 14Excluded economic studies

Study	Reason for Exclusion
Eke A, Buras A, Drnec S, Woo J. Vaginal progesterone versus cervical cerclage for the prevention of preterm births in women with a sonographically short cervixea cost effectiveness and decision analysis. American Journal of Obstetrics and Gynecology, S37–38 2015	Available as abstract only
Fonseca EB, Nishikawa AM, Paladini L, Clark O AC. Cervical Assessment With Progesterone in the Prevention of Preterm Birth: A Strategy Based On Cost-Effectiveness. Value in Health 2014 [PubMed: 27201568]	Considers cost-effectiveness of screening for preterm delivery, which is not being considered in this question.
Pizzi LT, Seligman NS, Baxter JK, Jutkowitz E, Berghella V. Cost and cost effectiveness of vaginal progesterone gel in reducing preterm birth: an economic analysis of the PREGNANT trial. PharmacoEconomics 32: 467 2014 [PubMed: 24715602]	Not cost-utility analysis. Cost-effectiveness analysis but of limited applicability because of US setting and definition of key outcome (pre-term birth).
Shree R, Page J, Caughey AB, Chandrasekaran S. Vaginal progesterone for preterm birth prevention in women with a short intepregnancy interval: A cost-effectiveness analysis. American journal of obstetrics and gynecology S227 2017	Available as abstract only
Soto Molina H, Diaz-Alvarez O, Sandoval-Avila M, Mejia D, Ramirez A, Rodriguez-Mendoza M M. Complete Economic Evaluation of the Use of Micronized Progesterone By Vaginal Administration for the Prevention of Preterm Birth in Pregnant Patients with Short Cervix in Mexico. Value in Health 21: S144 2018	Available as abstract only

Table 15Research recommendation rationale

Research question	Does progesterone reduce the risk of preterm birth in women who have risk factors for preterm birth, but do not have a short cervix (cervical length ≥25mm)?
Importance to ‘patients’ or the population	This question is important to women to guide treatment recommendations. It would enable vaginal progesterone to be offered appropriately to women at high risk, and avoid unnecessary treatment of women who may not be at such high risk of preterm birth.
Relevance to NICE guidance	The NICE guideline currently recommends consideration should be given to the use of progesterone for women with a short cervix or previous history of preterm birth.
Relevance to the NHS	Identifying women most at risk of preterm birth, and offering appropriate prophylaxis (such as vaginal progesterone) has the potential for significant cost savings, by reducing the incidence of preterm birth.
National priorities	60,000 babies are born prematurely each year, many of whom will require specialist neonatal care, often for many weeks or months. The report on the impact of preterm birth, Born too Soon (WHO, 2012) identifies the short-term consequences both on babies’ development and on their families, as well as the possible long-term consequences which can include life-long disabilities.
Current evidence base	Current evidence suggests a benefit of vaginal progesterone for women with a previous preterm birth, and for women with a short cervix (≤25mm). However, it is not clear to what extent these populations overlap. It is possible that vaginal progesterone is not of benefit for women in whom the cervix is found to be >25mm.
Equality	Cervical length scanning is not a routine part of antenatal care, therefore vaginal progesterone may be offered more commonly in units where this scan takes place, resulting in inequalities in care.

Table 16Research recommendation modified PICO table

Criterion	Explanation
Population	Women who have had a previous premature birth and have cervical length >25mm
Intervention	Use of vaginal progesterone in pregnancy
Prognostic or risk factor	Previous premature birth, less than 34 weeks’ gestation
Comparator (without the risk factor)	No vaginal progesterone/placebo
Outcome	Incidence of premature birth prior to 34 weeks’ gestation Neonatal outcomes
Study design	Randomised controlled trial or IPD meta-analysis
Timeframe	Minimum duration of follow up: until discharge

Table 17Research recommendation rationale

Research question	Does progesterone reduce the risk of preterm birth in women who have a cervical length ≤25mm, but no history of preterm birth?
Importance to ‘patients’ or the population	This question is important to women to guide treatment recommendations. It would allow vaginal progesterone to be offered appropriately to women at high risk of preterm birth, and avoid unnecessary treatment of women who may not be at such high risk of preterm birth.
Relevance to NICE guidance	The NICE guideline currently recommends consideration should be given to the use of progesterone for women with a cervical length ≤25mm or previous history of preterm birth.
Relevance to the NHS	Identifying women most at risk of preterm birth, and offering appropriate prophylaxis (such as vaginal progesterone) has the potential for significant cost savings, by reducing the incidence of preterm birth.
National priorities	60,000 babies are born prematurely each year, many of whom will require specialist neonatal care, often for many weeks or months. The report on the impact of preterm birth, Born too Soon (WHO, 2012) identifies the short-term consequences both on babies’ development and their families, as well as the possible long-term consequences which can include life-long disabilities.
Current evidence base	Current evidence suggests a benefit of vaginal progesterone for women with a previous preterm birth, and for women with a short cervix (≤25mm). However, it is not clear to what extent these populations overlap. It is possible that vaginal progesterone is not of benefit for women in whom the cervical length is ≤25mm, but who do not have a history of preterm birth.
Equality	Cervical length scanning is not a routine part of antenatal care, therefore vaginal progesterone may be offered more commonly in units where this scan takes place, resulting in inequalities in care.

Table 18Research recommendation modified PICO table

Criterion	Explanation
Population	Women who have a cervical length ≤25mm but no previous history of preterm birth
Intervention	Use of vaginal progesterone in pregnancy
Prognostic or risk factor	Cervical length ≤25mm
Comparator (without the risk factor)	No vaginal progesterone/placebo
Outcome	Incidence of premature birth prior to 34 weeks’ gestation Neonatal outcomes
Study design	Randomised controlled trial or IPD meta-analysis
Timeframe	Minimum duration of follow up: until discharge

Table 19Research recommendation rationale

Research question	At what gestation should treatment with prophylactic vaginal progesterone for the prevention of preterm birth be started and stopped?
Importance to ‘patients’ or the population	For some women, progesterone has clearly been shown to reduce the risk of preterm birth. However, it is unclear when this treatment should be started, and for how long it should be continued.
Relevance to NICE guidance	The current guideline recommends the use of progesterone during pregnancy for some women considered to be at high risk of preterm birth. Committee members noted that this guidance should recommend when treatment should be started and stopped, but no evidence was identified to address this issue.
Relevance to the NHS	Treatment with progesterone has the potential to reduce the incidence of preterm birth if used correctly. The most cost effective use of progesterone would be to use it for the shortest duration, timed to be of maximal benefit.
National priorities	60,000 babies are born prematurely each year, many of whom will require specialist neonatal care, often for many weeks or months. The report on the impact of preterm birth, Born too Soon (WHO, 2012) identifies the short-term consequences both on babies’ development and their families, as well as the possible long-term consequences which can include life-long disabilities.
Current evidence base	A number of studies have identified the value of progesterone for certain groups of women, but they vary in the gestation at which progesterone was started (and stopped). There is therefore a lack of evidence regarding which is the optimal gestation at which to use progesterone.
Equality	There is considerable variation in the timing of progesterone administration at present, and this may result in some women being provided with more effective care than others.

Table 20Research recommendation modified PICO table

Criterion	Explanation
Population	Women with risk factors for premature birth
Intervention	Vaginal progesterone started during early pregnancy (e.g. ≤16 weeks) and stopped at 34 weeks
Prognostic or risk factor	Preterm birth, less than 34 weeks gestation
Comparator (without the risk factor)	Vaginal progesterone started during early pregnancy (e.g. ≤16 weeks) and stopped at 36 weeks Vaginal progesterone started later in pregnancy (e.g. ≥20 weeks) and stopped at 34 weeks Vaginal progesterone started later in pregnancy (e.g. ≥20 weeks) and stopped at 36 weeks
Outcome	Preterm birth <34 weeks Neonatal outcomes
Study design	Randomised controlled trial.
Timeframe	Minimum duration of follow up: until discharge from hospital

Preterm labour and birth

Authors

Review question: What is the clinical effectiveness of prophylactic progesterone (vaginal or oral) in preventing preterm labour in pregnant women considered to be at risk of preterm labour and birth?

Introduction

Summary of the protocol

Methods and process

Clinical evidence

Included studies

Excluded studies

Summary of clinical studies included in the evidence review

Quality assessment of clinical studies included in the evidence review

Economic evidence

Economic model

Evidence statements

Comparison 1. Vaginal progesterone versus placebo

Critical outcomes

Preterm birth <34+0 weeks’

Subgroup analysis: Women with a history of spontaneous preterm birth

Subgroup analysis: Women with a short cervix (<30 mm)

Women with a short cervix (≤25 mm)

Stillbirth

Subgroup analysis: Women with a history of spontaneous preterm birth

Women with a short cervix (≤25 mm)

Infant mortality

Subgroup analysis: Women with a history of spontaneous preterm birth

Subgroup analysis: Women with a short cervix (<30 mm)

Women with a short cervix (≤25 mm)

Important outcomes

Gestational age at birth (mean weeks’)

Subgroup analysis: Women with a history of spontaneous preterm birth

Women with a short cervix (≤25 mm)

Neonatal sepsis

Subgroup analysis: Women with a history of spontaneous preterm birth

Subgroup analysis: Women with a short cervix (<30 mm)

Women with a short cervix (≤25 mm)

Health-related quality of life (measured with Euro-QoL-5 Dimensions health utility scores)

Change from baseline to birth

Change from baseline to 12 months

Health-related quality of life (measured with SF-36); women with a history of spontaneous preterm birth

General health domain

Social functioning domain

Emotional role domain

Mental health domain

Bayley-III cognitive composite score (2 years follow-up)

Women with a short cervix (≤25 mm)

Moderate or severe neurodevelopmental impairment (2 years follow-up)

Women with a short cervix (≤25 mm)

Hearing impairment

Visual impairment

Visual or hearing impairment (2 years follow-up); women with a short cervix (≤25 mm)

Comparison 2. Oral progesterone versus placebo

Critical outcomes

Preterm birth <34+0 weeks’

Infant mortality

Important outcomes

Gestational age at birth (mean weeks’)

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The quality of the evidence

Benefits and harms

Cost effectiveness and resource use

Other factors the committee took into account

References

Appendix A. Review protocols

Appendix B. Literature search strategies

Review question search strategies

Health economics search strategies

Appendix C. Clinical evidence study selection

Figure 1Flow diagram of clinical article selection for clinical effectiveness of prophylactic progesterone in preventing preterm labour

Appendix D. Clinical evidence tables

Appendix E. Forest plots

Comparison 1. Vaginal progesterone versus placebo

Critical outcomes

Figure 1Preterm birth <34+0 weeks

Figure 2Stillbirth

Figure 3Infant mortality

Important outcomes

Figure 4Gestational age at birth (mean weeks)

Figure 5Neonatal sepsis

Preterm birth <34⁺⁰ weeks’

Preterm birth <34⁺⁰ weeks’