Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

The EPPPIC Group

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116 Citations (Scopus)

Abstract

Background Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes. Methods We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299. Findings Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68–0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68–1·01), and oral progesterone (two trials, 183 women; 0·60, 0·41–0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84–1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92–1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15–2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC. Interpretation Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence. Funding Patient-Centered Outcomes Research Institute.
Original languageEnglish
Pages (from-to)1183-1194
Number of pages12
JournalThe Lancet
Volume397
Issue number10280
Early online date25 Mar 2021
DOIs
Publication statusPublished - 27 Mar 2021

Bibliographical note

Funding Information:
Research reported in this article was funded through a Patient-Centered Outcomes Research Institute (PCORI) award, PPA-1608-35707. The views presented are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its Board of Governors or Methodology Committee. Through two of its employees, PCORI had the opportunity to comment on the draft protocol and project outputs and was responsible for establishing the Advisory Group and for convening teleconferences and meetings. PCORI had no role in data collection or data analysis. March of Dimes funded meetings of the Secretariat and Advisory Group. One member of its staff was involved in establishing the Secretariat and had an opportunity to comment on the draft protocol, two members had opportunity to comment on project outputs.

Funding Information:
LAS and members of the research team are or were employees of the University of York, which received funding from the PCORI for the EPPPIC project. LD reports grants from the National Institute for Health Research (NIHR) programme for applied research, outside the submitted work. KD reports that her employer, Johns Hopkins Bloomberg School of Public Health, received funding through a sub-contract from York for patient engagement and conduct of the study of patient experience. MS and LAS report grants from the NIHR outside of the submitted work. No member of the project team was involved with any of the included trials or had any conflict of interest. SCB presented to the US Food and Drug Administration (FDA) Advisory Board on behalf of the sponsor (AMAG) regarding FDA approval of 17-OHPC. He did not receive any financial payments or financial support for this role. SNC reports grant support from AMAG to do a pharmacokinetic study on intramuscular versus subcutaneous 17-OHPC. AMAG also supplied 17-OHPC for a study he directs for the National Institute of Child Health and Human Development-sponsored Obstetric-Fetal Pharmacology Research Centers. CACr was lead investigator for the PROGRESS Trial, one of the studies included in the analysis. AFD reports personal fees from AMAG during the study and personal fees from Hologic outside the submitted work. BWM declared grants from the National Health and Medical Research Council, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, grants from Guerbet, and grants from Merck, outside the submitted work. JEN chaired the 2015 UK NICE Guideline on preterm labour and birth and received fees for this activity. She has received grants from government and charitable bodies for research into understanding the mechanism of term and preterm labour and understanding treatments. Within the past 3 years she has acted on a Data Safety and Monitoring Board for a study involving a preterm birth therapeutic agent for GlaxoSmithKline and has provided consultancy for Dilafor on drugs to alter labour progress. JNo reports grants from University of Edinburgh and grants from University of Aberdeen, outside the submitted work. He was Deputy Chair of the UK NIHR Health Technology Assessment General Funding Committee 2016–19; and is Chair of the UK Medical Research Council/NIHR Efficacy and Mechanisms Evaluation Funding Committee (2019–present). JMO was involved in studies of progesterone gel treatment for preterm birth prevention sponsored by a maker of progesterone gel. He was a principal investigator for studies published in 2011 and 2007. He once served on Advisory Boards and as a consultant for Watson, a company with a financial interest in marketing vaginal progesterone gel for preterm birth prevention. He is a cofounder of a company interested in developing and marketing interventions to prevent preterm birth, but that entity does not have an approved or commercially available intervention to date. He and others are listed in a patent on the use of progesterone compounds to prevent preterm birth (USA Patent Number 7884093: Progesterone for the Treatment and Prevention of Spontaneous Preterm Birth). He has received other patents for devices to treat obstetric patients, including subpopulations at increased risk for preterm birth. He has not received any funds from a royalty agreement or licensing of any patent to date, nor has his university. AT and LR report grants from the Danish Medical Research Council, Fetal Medicine Foundation, Copenhagen University Hospital's Research Fund, Aase and Ejnar Danielsens Fund, Augustinus Fund, Ivan Nielsen Fund, Doctor Sofus Carl Emil Friis and wife Olga Doris Friis' Fund, The Simon Fougner Hartmanns Family Fund, Danish Medical Society in Copenhagen, AP Moeller Foundation, during the study. EPW and JMC worked for the PCORI at the time the work was competitively awarded and funded by PCORI. The disclosure provided by the corresponding author, is intended to transparently reassure readers that the investigator team had complete authority and independence over the study and there was no undue influence by PCORI through EPW or JMC. Other than the fact that trial investigators contributed data from their trials, no other member of the EPPPIC group declared any potential competing interests.

Funding Information:
We gratefully acknowledge the contribution of the late Professor John Morrison in providing data from NCT00811057 and the additional contribution of trial investigator Pratima Majhi. We thank all trial investigators and those working in their trial groups who provided data for analysis, answered queries and worked with us to understand their datasets including those responsible for NCT00422526 , NCT00615550 /PREGNANT, NCT00480402 , and NCT01031017 , who provided data for analysis but declined to be members of the author group. We thank AMAG for their support in releasing data from the PROLONG trial, the Mednax Center for Research, Education, Quality and Safety for providing data from the trials of twins and triplets by Combs and colleagues; and Allergan for locating and providing archived data for the trial by O'Brien. We very much appreciate the administrative and financial support of secretariat and group meetings provided by March of Dimes. We would also like to acknowledge funding from and the helpfulness and support of PCORI staff throughout the project. We gratefully acknowledge the contribution made by the thousands of women who participated in the trials on which our analyses are based. We thank Genie Han for her valued assistance in working with the consumer groups and individuals to identify interview participants. We also thank the women who took part in our interviews and shared their experience so frankly and willingly. We wish to acknowledge the contributions made in supporting the project by CRD's NIHR Systematic Review Training Fellows (funded by the National Institute for Health Research). We thank Melissa Harden who set up and maintained the EPPPIC website and Vanda Castle for administrative support.

Publisher Copyright:
© 2021 Elsevier Ltd

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