• About Us
    • Contact Us
    • Login
    • ObGFirst
  • COVID-19
  • Alerts
  • OB
  • 2T US Atlas
  • The Genome
  • GYN
    • GYN
    • Sexual Health
  • Primary Care
  • Your Practice
  • GrandRounds
  • My Bookshelf
  • Now@ObG
  • Media
About Us Contact Us Login ObGFirst
  • COVID-19
  • Alerts
  • OB
  • 2T US Atlas
  • The Genome
  • GYN
    • GYN
    • Sexual Health
  • Primary Care
  • Your Practice
  • GrandRounds
  • My Bookshelf
  • Now@ObG
  • Media
Alerts
CMECNE

FDA, SMFM and ACOG Respond to PROLONG Study Results: Does IM 17-OHPC Impact Preterm Delivery?

image_pdfFavoriteLoadingFavorite

Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Discuss the results of the PROLONG trial regarding the efficacy of IM 17-OHPC for the prevention of preterm birth
2. State the responses from SMFM and ACOG to the results and recommendations regarding incorporating these findings in to clinical care for women who are now pregnant with a prior history of preterm birth

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.


The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from 1/15/2020 through 07/15/2022, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Designated for 0.1 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

Read Disclaimer & Fine Print

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
    • Preterm birth <37 weeks: Relative risk (RR) 0.66 (95% CI, 0.54 to 0.81; P<.001)
    • Preterm births <35 weeks: RR 0.67 (95% CI, 0.48 to 0.93)
    • Preterm birth <32 weeks: RR 0.58 (95% CI, 0.37–0.91)
  • 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

Learn More – Primary Sources:

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth

ACOG Practice Advisory: Clinical guidance for integration of the findings of the PROLONG study: Progestin’s Role in Optimizing Neonatal Gestation

ACOG Statement on FDA Proposal to Withdraw 17p Hydroxyprogesterone Caproate

ACOG Practice Bulletin 130: Prediction and Prevention of Preterm Birth

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

FDA (October 2020): CDER proposes withdrawal of approval for Makena

Re-examining the Meis Trial for Evidence of False-Positive Results (Sibai et al. Obstetrics & Gynecology, 2020)

Take a post-test and get CME credits

TAKE THE POST TEST

Want to be notified when new guidelines are released? Get ObGFirst!

Learn More »

image_pdfFavoriteLoadingFavorite
< Previous
All Alerts Posts
Next >

Related ObG Topics:

Progesterone, Cerclage or Pessary for Prevention of Preterm Birth: A Comparison
Does Use of Progestogen Prolong Labor in PPROM Pregnancies?
Does a Weekly Dose of 17-OHPC Improve Outcomes in the Setting of Preterm Ruptured Membranes?
17-OHPC Treatment and Prevention of Preterm Birth: Does Timing Matter?
Do Progestogens Prevent Preterm Birth in Symptomatic Pregnancies with a Short Cervix?
How do Compounded vs. Commercial 170HP Formulations Compare?

Sections

  • COVID-19
  • Alerts
  • OB
  • GYN
    • GYN
    • Sexual Health
  • 2T US Atlas
  • The Genome
  • Primary Care
  • Your Practice
  • Grand Rounds
  • My Bookshelf
  • Now@ObG
  • Media

Are you an
ObG Insider?

Get specially curated clinical summaries delivered to your inbox every week for free

  • Site Map/
  • © ObG Project/
  • Terms and Conditions/
  • Privacy/
  • Contact Us/
© ObG Project
SSL Certificate


  • Already an ObGFirst Member?
    Welcome back

    Log In

    Want to sign up?
    Get guideline notifications
    CME Included

    Sign Up

Get Guideline Alerts Direct to Your Phone
Try ObGFirst Free!

Sign In

Lost your password?

Sign Up for ObGFirst and Stay Ahead

  • - Professional guideline notifications
  • - Daily summary of a clinically relevant
    research paper
  • - Includes 1 hour of CME every month

ObGFirst Free Trial

Already a Member of ObGFirst®?

Please log in to ObGFirst to access the 2T US Atlas

Password Trouble?

Not an ObGFirst® Member Yet?

  • - Access 2T US Atlas
  • - Guideline notifications
  • - Daily research paper summaries
  • - And lots more!
ObGFirst Free Trial

Media - Internet

Computer System Requirements

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

Subscribe

JOIN OBGFIRST AND GET CME/CE CREDITS

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

Learn More
Leaving ObG Website

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