Utilization of hydroxyprogesterone caproate among pregnancies with live birth deliveries in the sentinel distributed database

Abstract

Background

The U.S. Food and Drug Administration (FDA) approved Makena^® (hydroxyprogesterone caproate [HPC] injection) in February 2011 for reducing the risk of preterm birth (PTB) in women with a singleton pregnancy who had a history of singleton spontaneous PTB (sPTB). Makena was approved under accelerated approval and required a postmarketing study to verify its clinical benefits. However, the postmarketing trial (PROLONG) failed to verify Makena’s clinical benefit to neonates and substantiate its effect on reducing the risk of recurrent PTB. This study examined the utilization of HPC, along with another progestogen (vaginal progesterone) used to reduce the risk of sPTB during pregnancy, to inform the landscape of HPC use in the United States.

Methods

We included pregnant women aged 10–54 years with a live birth delivery from 1 January, 2008 to 31 December, 2018 in the Sentinel Distributed Database (SDD). We examined the prevalence of injectable HPC (Makena and its generics), compounded HPC, and vaginal progesterone use during the second and third trimesters during the study period. We also assessed the proportion of these HPC-exposed pregnancies with obstetrical conditions of interest as potential reasons for use: (1) history of preterm delivery; (2) cervical shortening in the current pregnancy; and (3) preterm labor in the current pregnancy.

Results

We identified a total of 3,445,739 live-birth pregnancies (among 2.9 million women) between 2008 and 2018 in the SDD. Of these pregnancies, 6.5 per 1,000 pregnancies used injectable HPC, 2.3 per 1,000 pregnancies used compounded HPC, and 1.5 per 1,000 pregnancies used vaginal progesterone during the second and/or third trimesters. The yearly uptakeof pregnancies with injectable HPC use increased during the study period from 2.1 per 1,000 pregnancies in 2012 to 12.6 per 1,000 pregnancies in 2018; use of compounded HPC decreased from 3.3 per 1,000 pregnancies to 0.25 per 1,000 pregnancies over the same period. Of 16,524 pregnancies with injectable HPC use, 12,054 (73%) had at least one related obstetrical condition, including 6,439 (39%) with a recorded history of preterm delivery. In addition, 4,665 (28%) had a PTB recorded as the outcome for the current pregnancy.

Conclusions

We found modest use of HPC during the second and/or third trimesters among all live-birth pregnancies in SDD. The majority of pregnancies with injectable HPC use had at least one of three obstetrical indications of interest recorded before or during the pregnancy.

Keywords:

• Hydroxyprogesterone Caproate
• preterm birth
• pregnancy
• Sentinel
• FDA

Acknowledgements

We thank those who participated in this project: Data Partners who provided data used in the analysis: Aetna, a CVS Health company, Blue Bell, PA; Blue Cross Blue Shield of Massachusetts, Boston, MA; Harvard Pilgrim Health Care Institute, Boston, MA; HealthCore, Inc., Translational Research for Affordability and Quality, Alexandria, VA; HealthPartners Institute, Minneapolis, Minnesota; Humana, Inc., Healthcare Research, Miramar, FL; Kaiser Permanente Colorado Institute for Health Research, Denver, CO; Kaiser Permanente Center for Health Research Hawai’i, Honolulu, HI; Kaiser Permanente Mid-Atlantic States, Mid-Atlantic Permanente Research Institute, Rockville, MD; Kaiser Permanente Northern California, Division of Research, Oakland, CA; Kaiser Permanente Northwest Center for Health Research, Portland, OR; Kaiser Permanente Washington Health Research Institute, Seattle, WA; Marshfield Clinic Research Institute, Marshfield, WI; Meyers Primary Care Institute, Worcester, MA; OptumInsight Life Sciences Inc., Boston, MA; Vanderbilt University Medical Center, Department of Health Policy, Nashville, TN, through the TennCare Division of the Tennessee Department of Finance & Administration which provided data.

Ethics approval

This project meets the definition of a Public Health Surveillance activity described in 45 CFR 46.102(l)(2) and is deemed not to be research under the 2018 Requirements of the Common Rule.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Disclaimer

The views expressed in this article are those of the authors and are not intended to convey official U.S. Food and Drug Administration policy or guidance.

Prior presentation

Findings from this study were presented as an oral presentation at the 36^th International Conference of Pharmacoepidemiology and Therapeutic Risk Management (ICPE), virtual event, September 2020.

Notes

1 Preterm labor refers to uterine contractions resulting in cervical change that occur prior to 37 weeks gestation. In most cases, however, preterm labor resolves and does not result in a preterm birth.

Additional information

Funding

The Sentinel Initiative is funded by the U.S. Food and Drug Administration through the Department of Health and Human Services contract HHSF223201400030I. The Sentinel System (Harvard Pilgrim Health Care Institute and the participating Data Partners) had full access to the study data and were responsible for the collection, management and integrity of the data and data analysis programs. The FDA and Sentinel investigators designed the analysis, interpreted the results, and prepared, reviewed and approved the final manuscript.