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Evaluating Hormone Treatments for Women at Increased Risk for Preterm Birth – EPPPIC

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Results Summary and Professional Abstract

Results Summary
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Results Summary

What was the research about?

A full-term pregnancy lasts about 40 weeks. In preterm birth, a baby is born before 37 weeks. When babies are born too soon, they are at higher risk for health problems, like difficulty breathing or feeding. Babies who are born before 34 weeks are also more likely than full-term babies to die during their first year.

Progestogens are hormones made by women’s bodies that help support pregnancy. They may help reduce the risk of preterm birth. In this study, the research team analyzed data from 30 previous studies to examine two types of hormone treatments for pregnant women who were at risk for preterm birth:

  • 17-OHPC, a hormone made in a lab and injected
  • Vaginal progesterone, a natural hormone given through a gel or tablet in the vagina

What were the results?

Women pregnant with one baby. Compared with getting no hormones, women with a short cervix or previous preterm birth who received either 17-OHPC or vaginal progesterone

  • Had a lower chance of their baby being born before 34 weeks
  • Might have a lower chance of their baby dying or having serious problems
  • Might have more health problems

The study found no evidence that either 17-OHPC or vaginal progesterone was better than the other in reducing

  • Preterm birth before 34 weeks
  • Women’s health problems
  • Newborns’ health problems

Women pregnant with twins or triplets. Compared with no hormones, the study found no evidence that either 17-OHPC or vaginal progesterone reduced the chances of preterm birth before 34 weeks, or women’s or newborns’ health problems for women with no other risk factors.

Who was in the study?

Researchers analyzed 30 trials, which included 9,936 women at increased risk for preterm birth and their 14,477 babies. Most women who were pregnant with one baby either had a previous preterm birth or a short cervix. Most women who were pregnant with twins or triplets didn’t have other risk factors.

What did the research team do?

The research team combined data from the trials and analyzed it together. Combining data from multiple trials provides more reliable results that just looking at single trials. The team compared the treatments to no treatment and to each other using these data, to see how well they reduced preterm birth and women’s and babies’ health problems.

Women who had given birth preterm and members of patient and family advocacy organizations gave input on the study.

What were the limits of the study?

The research team could not be certain about the treatments’ effects on serious problems for babies or mothers, as these problems happened only rarely in the trials. Also, only two trials directly compared 17-OHPC and vaginal progesterone.

After the team completed their analysis, other researchers published results from a large trial looking at women receiving 17-OHPC. If this trial was included, the study results for 17-OHPC might change. Future research could update the study with results from this large trial.

How can people use the results?

Doctors and women at risk for preterm birth can use these results when talking about options to help reduce the chance of their babies being born preterm.

Professional Abstract

Professional Abstract

Objective

To evaluate the effectiveness of progestogens versus placebo or no intervention in reducing preterm birth (PTB) and associated maternal and neonatal complications 

Study Design

Design Element Description
Design IPD meta-analysis
Population 5,598 women with a singleton pregnancy at risk for PTB mostly due to prior PTB or short cervix; 4,338 women with multifetal pregnancy, mostly with no other risk factors
Interventions/
Comparators
  • Injectable 17-OHPC (a synthetic hormone) versus placebo or no intervention
  • Vaginal progesterone (a natural hormone) versus placebo or no intervention
  • Oral progesterone (a natural hormone) versus placebo or no intervention
  • Injectable 17-OHPC versus vaginal progesterone
Outcomes PTB before 28, 34, and 37 weeks; perinatal death; serious neonatal complications; maternal complications
Timeframe Not applicable

This individual participant data (IPD) meta-analysis compared the effectiveness of progestogens versus placebo or no intervention in reducing PTB and associated neonatal and maternal complications.

Researchers searched bibliographic databases and international registries for published and unpublished randomized controlled trials completed prior to July 2016. They invited trial investigators to join a collaborative group and supply their data sets for re-analysis. The IPD meta-analysis included 30 trials with data from 9,936 women and 14,477 babies.

Researchers analyzed singleton and multiple gestation pregnancies separately and compared each form of progestogen with placebo or no intervention. They then compared injectable 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone using network meta-analysis.

Women who had experienced PTB and members of patient and family advocacy organizations were part of the collaborative group.

Results

Singleton pregnancies at high risk for PTB, mostly due to prior PTB or short cervix.

Compared with untreated women, women who received injectable 17-OHPC

  • Were less likely to have babies who were born before 34 weeks (risk ratio [RR]=0.74; 95% confidence interval [CI]: 0.59, 0.94)
  • Had reduced risk of perinatal death, but this was very uncertain (RR=0.88; 95% CI: 0.54, 1.45)
  • Were more likely to experience maternal complications (RR=1.34; 95% CI: 1.06, 1.71)
  • Had babies with reduced risk of serious neonatal complications, but this was uncertain (RR=0.76; 95% CI: 0.54, 1.08)

Compared with untreated women, women who received vaginal progesterone

  • Were less likely to have babies who were born before 34 weeks (RR=0.78; 95% CI: 0.68, 0.90)
  • Had reduced risk of perinatal death, but this was uncertain (RR=0.74; 95% CI: 0.52, 1.07)
  • Were more likely to have maternal complications, but this was uncertain (RR=1.14; 95% CI: 0.93, 1.40)
  • Had babies with reduced risk of serious neonatal complications, but this was uncertain (RR=0.82; 95% CI: 0.65, 1.04)

Comparing 17-OHPC with vaginal progesterone, network meta-analysis found no clear evidence that either was more effective in reducing PTB before 34 weeks, serious neonatal complications, overall maternal complications, or perinatal death.

Evidence for oral progesterone was insufficient.

Multiple gestation pregnancies, mostly with no additional risk factors

Overall, the study found no evidence that 17-OHPC or vaginal progesterone reduced PTB before 34 weeks or associated complications in unselected multifetal pregnancies. Data were too few for reliable analysis of women with additional risk factors.

Limitations

A large trial of 17-OHPC in singleton pregnancies was completed after this meta-analysis. Incorporating these and other new trial data could change the estimated effects. Only two trials directly compared 17-OHPC with vaginal progesterone. The meta-analysis mainly used indirect evidence from trials comparing progestogens with placebo or no treatment.

Conclusions and Relevance

For women with singleton pregnancies with a previous PTB or short cervix, both 17-OHPC and vaginal progesterone reduced the risk of PTB before 34 weeks and improved other birth and neonatal outcomes. However, 17-OHPC increased overall maternal complications. Maternal complications also increased with vaginal progesterone, but this effect was smaller and more uncertain. The findings do not support the use of progestogens in unselected twin or triplet pregnancies.

Future Research Needs

This meta-analysis should be updated to include newly completed trials, including the recent large trial of 17-OHPC. Depending on the results of an update, further trials comparing vaginal progesterone, 17-OHPC, and potentially oral progesterone may be needed.

This project's final research report is expected to be available by October 2020.

Journal Articles

Related Articles

Systematic Reviews

Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol

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Protocol for this Review

Peer-Review Summary

Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.

The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments. 

Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:

  • The reviewers commented that a limitation of the report is that it excluded observational studies, especially ones considering subgroups and neurodevelopmental outcomes. The researchers said they did not try to collect data from observational studies because of budget and time constraints but agreed that a future review of observational studies would be a useful addition to the evidence already collected. The researchers also revised the report to acknowledge that other trials of preterm birth preventive treatments have ended since they completed the current meta-analysis. However, these newer trials have not provided the individual patient data necessary for inclusion in the type of analysis described in this report. Once this information is available, the researchers hope to include the additional trials in an update to the current report.
  • The reviewers noted that there did not appear to be much patient and stakeholder engagement in this study, as is typical for PCORI-funded research. The researchers acknowledged that it was difficult to incorporate patient and stakeholder feedback in the study. They stated that given that this project was a meta-analysis combining data from already-completed clinical trials, there was little relevant support and guidance patient and stakeholder partners could provide. Instead, the researchers added a qualitative component to the study to gain information about patient perspectives related to treatment options for preterm birth, to help put the study results into perspective.
  • The reviewers questioned the presentation of the qualitative substudy, stating that the researchers presented the results in a way that made them seem like a minor portion of the work. The researchers said they tried to strengthen the patient voice in the study by conducting a small-scale qualitative analysis, which they believe provided insights that were integral to the report’s conclusions and recommendations. The researchers restructured the report so that a summary of the qualitative study methods is in the main report and much more detailed information is in an appendix.
  • The reviewers asked for a clearer explanation of how the researchers handled missing data. The researchers said they did not need to infer missing data since sets of variables were generally provided in their entirety or were completely missing in any one trial.

Conflict of Interest Disclosures

View the COI disclosure form.

Project Details

Principal Investigator
Lesley Stewart, PhD, MSc
Project Status
Completed; PCORI Public and Professional Abstracts Posted
Project Title
Evaluating Progestogen for Prevention of Preterm Birth International Collaborative (EPPPIC): Individual Participant Data Meta-Analysis
Project End Date
December 2020
Organization
University of York (United Kingdom)
Year Awarded
2017
Year Completed
2019
Project Type
Research Project
Populations
Children -- 18 and under
Women
Project Budget
$581,286
Study Registration Information
HSRP20181696
Page Last Updated: 
December 10, 2020