ACOG Menu

Clinical Guidance for Integration of the Findings of the PROLONG Study: Progestin’s Role in Optimizing Neonatal Gestation

  • Practice Advisory PA
  • October 2019

This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics in collaboration with Mark Turrentine, MD, Anjali Kaimal, MD, MAS, Hyagriv Simhan, MD, and Aaron B. Caughey, MD, PhD.


A trial comparing the efficacy of 17-alpha-hydroxyprogesterone caproate (17-OHPC) 250 mg intramuscular injection weekly compared with placebo on both preterm birth and neonatal morbidity among women with a singleton pregnancy and prior spontaneous preterm birth was published in the American Journal of Perinatology on October 25, 2019 1. The study was a large international multicenter, randomized, controlled, double blind trial conducted from November 2009 to October 2018 that evaluated 1,877 eligible women, of which 1,740 provided informed consent and underwent randomization. The trial was conducted at 93 facilities across 9 countries associated with a hospital that had access to a Level 3 or greater Neonatal Intensive Care Unit. Twenty-three percent of women were enrolled from the United States. Women were randomized between 16 0/7 to 20 6/7 weeks of gestation with greater than 91% of participants adhering to the assigned protocol, with no differences in the number of study medication injections between those receiving 17-OHPC or placebo (both groups with a median of 18, range 1-22).

This study demonstrated no statistical difference in the co-primary outcome of preterm birth less than 35 0/7 weeks of gestation (17-OHPC 11.0% versus 11.5%; Relative Risk [RR] 0.95 [95% CI 0.71-1.26]; P = 0.72) and neonatal composite index (17-OHPC 5.6% versus 5.0%; RR 1.12 [95% CI 0.70-1.66]; P = 0.73). Similarly, the rate of preterm birth less than 37 weeks and less than 32 weeks were not different. No other differences in perinatal or maternal outcomes were detected. However, despite having the same eligibility criteria and study protocol as the trial by Meis et al in 2003 that provided randomized trial evidence for 17-0HPC for the prevention of recurrent preterm birth 2, the patient populations had divergent sociodemographic characteristics and a substantially lower preterm birth rate when compared with the prior study 1 2. Based on these results, the authors suggest that the PROLONG trial was underpowered to assess treatment efficacy related to preterm birth and neonatal outcomes in this population. Further, due to guidance published in 2008, a possible unintentional selection bias may have occurred in women enrolled in the United States that resulted in women with a higher risk for recurrent preterm birth not being offered or agreeing to participate in the PROLONG study in order to avoid the risk of not receiving active 17OPHC treatment.

Current guidelines in the United States recommend the use of progesterone supplementation in women with prior spontaneous preterm birth 3. Consideration for offering 17-OHPC to women at risk of recurrent preterm birth should continue to take into account the body of evidence for progesterone supplementation, the values and preferences of the pregnant woman, the resources available, and the setting in which the intervention will be implemented. Additional information from planned meta-analysis and secondary analyses will need to be evaluated to assess the impact this intervention has on women at risk of recurrent preterm birth in the United States. ACOG is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130, Prediction and Prevention of Preterm Birth 3.

ACOG will be reviewing subsequent forthcoming analyses and will issue updated clinical guidance as appropriate.


References

  1. Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, Chauhan SP, Hughes BL, Louis JM, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial [published ahead of print]. Am J Perinatol 2019;DOI: 10.1055/,3400227.
    Article Locations:
    Article Location
  2. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate [published erratum appears in N Engl J Med 2003;349:1299]. N Engl J Med 2003;348:2379-85.
    Article Locations:
    Article LocationArticle Location
  3. Prediction and prevention of preterm birth. Practice Bulletin No. 130. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:964-73.
    Article Locations:
    Article Location



A Practice Advisory is issued when information on an emergent clinical issue (e.g. clinical study, scientific report, draft regulation) is released that requires an immediate or rapid response, particularly if it is anticipated that it will generate a multitude of inquiries. A Practice Advisory is a brief, focused statement issued within 24-48 hours of the release of this evolving information and constitutes ACOG clinical guidance. A Practice Advisory is issued only on-line for Fellows but may also be used by patients and the media. Practice Advisories are reviewed periodically for reaffirmation, revision, withdrawal or incorporation into other ACOG guidelines. 

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.

While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither ACOG nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.

Publications of the American College of Obstetrician and Gynecologists are protected by copyright and all rights are reserved. The College's publications may not be reproduced in any form or by any means without written permission from the copyright owner. 


The American College of Obstetricians and Gynecologists (ACOG), is the nation's leading group of physicians providing health care for women. As a private, voluntary, nonprofit membership organization of more than 58,000 members, ACOG strongly advocates for quality health care for women, maintains the highest standards of clinical practice and continuing education of its members, promotes patient education, and increases awareness among its members and the public of the changing issues facing women's health care. www.acog.org