EPPPIC Meta-analysis Results: Progestogens for Preterm Birth Prevention
PURPOSE:
The EPPPIC group (Lancet, 2021) report on their systematic review of RCTs comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone for prevention of preterm birth
METHODS:
Systematic review and meta-analysis
Funded by Patient-Centered Outcomes Research Institute (PCORI)
Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC)
Study selection
Published and unpublished RCTs
Trials that assessed vaginal progesterone, IM 17-OHPC or oral progesterone with control, or with each other
Participants: Asymptomatic women at risk of preterm birth
Individual participant data were requested from investigators of eligible trials
Primary data collection before July 30, 2016, (12 months before data collection began), and July 30, 2019
Exclusion: Trials of progestogen to prevent early miscarriage or immediatelythreatened preterm birth
Outcomes
Preterm birth | Early preterm birth | Mid-trimester birth
Adverse neonatal sequelae (composite of serious neonatal complications and individually)
Adverse maternal outcomes were investigated as a composite and individually
RESULTS:
Individual participant data available for 31 trials | 11,644 women and 16,185 offspring
Singleton
Risk factors and indications for treatment
Previous spontaneous preterm birth
Short cervix (≤25 mm)
Preterm birth <34 weeks was reduced in women receiving progestogen
17-OHPC (twins or triplets): RR 1.04 (95% CI, 0.92 to 1.18; 8 trials)
PPROM <34 weeks was higher with 17-OHPC
RR 1.59 (95% CI, 1.15 to 2.22
Evidence for other outcomes (risks or benefits) was not seen for vaginal progesterone or 17-OHPC
CONCLUSION:
Preterm birth <34 weeks was reduced with vaginal progesterone and 17-OHPC in high risk pregnancies
Absolute risk reduction is greater for women with a short cervix
Evidence in this study did not support use of oral progesterone or treatment for unselected multifetal pregnancy
An editorial suggests
This current meta-analysis supports “the use of either 17-OHPC or vaginal progesterone to prolonged pregnancy, even with the inclusion of the negative findings from PROLONG”
There are other trials currently underway and therefore this study should be considered a ‘living’ meta-analysis
The EPPPIC authors conclude
Evidence of benefit in reducing preterm birth before 34 weeks was more certain for vaginal progesterone, but there was no clear evidence that either vaginal progesterone or 17-OHPC was superior
A consistent direction of benefit was noted for other birth and neonatal outcomes, including preterm birth before 28 weeks, preterm birth before 37 weeks, perinatal mortality, and composite serious neonatal complications
Response from SMFM and ACOG:
SMFM
EPPPIC reinforces current SMFM guidelines
Singleton pregnancy and a short cervix (<25 mm) without a history of a prior spontaneous preterm birth
Offer vaginal progesterone
Singleton gestation and a history of prior spontaneous preterm birth between 20 weeks and 36w6d
SMFM recommends “consideration of the use of 17-OHPC”
ACOG
ACOG notes that while 17-OHPC didn’t quite reach significance, the authors did not see a clear difference between route of administration, nor indication for treatment
ACOG states
Patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared-decision making process with the patient incorporating the available evidence and the patient’s preferences
With regard to multiple gestations, the Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC) findings support the current recommendation that progesterone supplementation is not indicated for the indication of multiple gestation alone as there is no evidence of benefit
Response from FDA:
The FDA has responded to EPPPIC and has not altered the recommendation to withdraw approval from Makena
The FDA states
The EPPPIC meta-analysis grouped together HPC trials of patients with differences in their risk profiles, including combining women with a prior PTB and those without a prior PTB, and women with and without a short cervix
Because of this grouping, the meta-analysis does not provide relevant information regarding Makena’s effectiveness for its approved use. CDER continues to conclude the available data have not shown Makena is effective for reducing morbidity or mortality in newborns or for the prevention of recurrent PTB in women with a prior spontaneous PTB
FDA, SMFM and ACOG Respond to PROLONG Study Results: Does IM 17-OHPC Impact Preterm Delivery?
This entry has been updated with the latest FDA proposed decision and a summary of the review by Sibai et al. (Obstet Gynecol, 2020)
SUMMARY:
The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)
In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death
On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. The CDER proposal announcement further states
Makena and its approved generic equivalents will remain on the market until the manufacturers decide to remove the drugs or the FDA Commissioner mandates their removal
If AMAG Pharmaceuticals requests a hearing, the FDA Commissioner will determine whether to hold a public hearing and, following such hearing, decide whether to withdraw approval of Makena and its approved generic equivalents
In the interim, we recommend that health care professionals discuss Makena’s benefits, risks and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status
We intend to hold a meeting with experts in obstetrics, neonatal care, and clinical trial design to discuss how to facilitate development of effective and safe therapies to treat preterm birth
Background to PROLONG Trial
A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHPC in preventing PTB (see ‘Learn More – Primary Sources)
Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway
PROLONG Methods
Double-blind randomized controlled trial (RCT)
Participants
≥18 years
Singleton pregnancy
Currently 16w0d to 20w6d
Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
Groups (IM injection 1 in upper outer quadrant of the gluteus maximus) weekly until delivery or 36 weeks
17-OHPC (250 mg)
Placebo
Stratified by
Study site
GA at randomization
Primary outcomes
PTB < 35 weeks
Composite neonatal morbidity and mortality index
PROLONG Results
PTB < 35w0d (p=0.72)
17-OHPC: 11.0%
Placebo: 11.5%
Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
Neonatal composite index (p=0.73)
17-OHPC 5.6%
Placebo 5.0%
RR 1.12 (95% CI, 0.70–1.66)
Note: No differences seen in any of the individual components that were part of the composite index
KEY POINTS:
SMFM Response
SMFM has responded to the PROLONG trial results and makes the following substantive points comparing current data to Meis et. al. study
Difference in population when analyzing Meis et al., vs PROLONG
Higher rate of black women: 59% vs 7%
Smoking (tobacco): >20% vs 8%
>1 prior PTB: 32% vs 12%
Additional PTB risk factors aside from prior history: 91% vs 48%
Difference in results may be a result of high vs average risk but “population differences do not completely explain the discrepancy” due to complexity of PTB
Concerns related to 17-OHPC include
Healthcare costs
Injection-site pain
Additional patient visits
Additional research required to (1) determine long-term maternal and neonatal side effects (2) “identify populations in which administration of 17-OHPC may provide needed benefit in the reduction of recurrent sPTB”
SMFM states that
…it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit
ACOG Response
ACOG has likewise responded to the PROLONG trial with a Practice Advisory | Guidance remains unchanged following the FDA decision
Similar to SMFM, ACOG notes that while eligibility criteria were similar between the Meis trial and PROLONG, the populations are different and preterm birth rate in the current study is approximately 50% lower than the earlier study
The study authors acknowledge that
PROLONG may be underpowered for the population under study
Selection bias may have played a role, as women at higher risk would not have agreed to possibility of receiving placebo
Additional studies, including a meta-analysis, are planned
ACOG Guidance (Practice Bulletin 130) states
A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth
The Practice Advisory response to the PROLONG trial states that ACOG
is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130
Sibai et al. Obstet Gynecol, 2020
Meis Trial
Well designed and conducted
Highly statistically significant results
Prespecified criterion threshold of alpha=0.015 was met regarding benefit of 17-OHPC
Subgroup analysis: Number of prior preterm birth | Race | Marital status | Smoking or substance use
Confirmed generalizability
Prolong Trial
Population studied was very different from that of the Meis trial (non-US)
Trial is underpowered based on observed event rates
For 90% power, PROLONG required 3,600 women for preterm birth <35 weeks and 6,000 women for neonatal composite outcome
PROLONG not powered for subgroup analysis, but Meis et al. did look at US subgroup and found that while not statistically significant
Direction and magnitude of effect <32 weeks and neonatal composite index were similar to the Meis trial
Authors’ Conclusion
We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study
Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health
Does Use of Progestogen Prolong Labor in PPROM Pregnancies?
BACKGROUND AND PURPOSE:
Progestogen use appears to prolong pregnancy in women with previous spontaneous preterm birth and short cervical length
Quist-Nelson et al. (AJOG, 2018) sought to determine whether progestogen use in singleton pregnancies prolongs pregnancy after preterm prelabor rupture of membranes (PPROM)
METHODS:
Systematic review and meta-analysis
Database search of RCTs
Singleton gestations deliveries following PPROM
PPROM: Defined <37 weeks
Patients had received
Progestogens (17 alpha-hydoxyprogesterone caproate or natural progesterone)
Matched placebo or no treatment
Primary outcome: Time from randomization until delivery (latency)
Secondary outcomes
Preterm birth at <37, <34, <32, and <28 weeks | Mean gestational age at delivery | Mode of delivery | Endometritis, chorioamnionitis | Neonatal outcomes, such as birthweight, RDS, IVH etc.
Outcomes stratified by progestogen and route of administration
RESULTS:
Six RCTs were included | Totaling 545 participants
ACOG defines cervical insufficiency as “the inability of the uterine cervix to retain a pregnancy in the absence of the signs and symptoms of clinical contractions, or labor, or both in the second trimester.” In addition, ACOG separates out indication for cerclage in to 3 categories
History: ≥1 of the following
Second trimester pregnancy losses related to painless cervical dilation and no history of labor or abruption
Previous second trimester cerclage for painless cervical dilation
Physical Examination: Also known as ‘physical examination–indicated cerclage’, ‘rescue cerclage’ and ’emergency cerclage’
Patient presents with painless second trimester cervical dilation
Ultrasound: Cervical length shortening and history of preterm birth
Singleton pregnancy
Prior spontaneous preterm birth (<34 weeks)
Cervical length: <25 mm (at <24 weeks)
SMFM states that cerclages are effective in woman based on the following indications:
History indicated: 3 or more PTBs or second-trimester losses.
Ultrasound indicated: ≥1 early PTB (defined as delivery between 17w to 33w6d), and cervical length (CL) <25 mm on transvaginal ultrasound (TVUS) before 24 weeks
Timing of Cerclage Placement
History-indicated cerclage
Place between 12 and 14 weeks after confirmation of pregnancy viability
Ultrasound or exam-indicated cerclage
May be placed prior to 23 weeks
Risk Factors
Prior PTB
Repeated cervical dilation
Cervical procedures (including cone and LEEP)
Cervical laceration
Urogenital abnormalities
SYNOPSIS:
Clinically, cervical insufficiency is painless dilation and recurrent mid-trimester losses without signs of preterm labor (PTL), PPROM, or infection. Patient history may include superimposed symptoms (i.e. bleeding, pressure), therefore a judicious review of records is advised. Those with a history of prior preterm birth can benefit from cervical length screening to appropriate guide selected patients for cerclage.
KEY POINTS:
Ultrasound Indicated Cerclage with Prior History of Preterm Birth or Second Trimester Losses (SMFM)
CL surveillance
Begin at 16 weeks
Perform every 2 weeks
CL measurement 25-29 mm: Perform weekly
Offer cerclage when
CL <25 mm prior to 23w0d weeks and
History of spontaneous PTB at 17w0d to 33w6d
17–alpha hydroxyprogesterone caproate (17-OHPC)
Note: Cerclage placement or presence should not alter recommendations
Evidence from research studies
There is no difference in efficacy of McDonald versus Shirodkar techniques
Special Circumstances
Diagnosis of cervical insufficiency is unclear
Consider close screening starting at 16 weeks in place of history indicated cerclage placement
Very early losses
Consider beginning screening <16 weeks if there is a history of very early second trimester losses
‘Emergency’ Cerclage (Exam indicated)
There is literature, including a meta-analysis (Obstet Gynecol, 2015), to support ’emergency’ or ‘rescue’ cerclage
Neonatal survival
Cerclage: 71% survival
No cerclage: 43% survival
Relative risk 1.65 (95% CI 1.19–2.28)
Prolongation of pregnancy
Mean difference: 33.98 days (95% CI, 17.88 to 50.08)
Authors note significant limitations including quality of data and only 1 RCT included
After clinical examination to rule out uterine activity, or intraamniotic infection, or both, physical examination-indicated cerclage placement (if technically feasible) in patients with singleton gestations who have cervical change of the internal os may be beneficial
SMFM Choosing Wisely Campaign
SMFM recommends the following after cerclage placement
Do not perform serial cervical length measurements
There is no evidence that cervical length monitoring following a cerclage improves outcomes, despite cervical shortening being associated with increased risk for preterm birth
OBG Project CME requires a modern web browser (Internet Explorer 10+, Mozilla Firefox, Apple Safari, Google Chrome, Microsoft Edge). Certain educational activities may require additional software to view multimedia, presentation, or printable versions of their content. These activities will be marked as such and will provide links to the required software. That software may be: Adobe Flash, Apple QuickTime, Adobe Acrobat, Microsoft PowerPoint, Windows Media Player, or Real Networks Real One Player.
Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclaimer
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
Jointly provided by
NOT ENOUGH CME HOURS
It appears you don't have enough CME Hours to take this Post-Test. Feel free to buy additional CME hours or upgrade your current CME subscription plan
One of the benefits of an ObGFirst subscription is the ability to earn CME/CE credits from the ObG entries you read. Tap the button to learn more about ObGFirst
You are now leaving the ObG website and on your way to PRIORITY at UCSF, an independent website. Therefore, we are not responsible for the content or availability of this site