Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth

Steve N Caritis¹, Raman Venkataramanan¹, Elizabeth Thom², Margaret Harper³, Mark A Klebanoff⁴, Yoram Sorokin⁵, John M Thorp Jr³, Michael W Varner⁶, Ronald J Wapner⁷, Jay D Iams⁸, Marshall W Carpenter⁹, William A Grobman¹⁰, Brian M Mercer¹¹, Anthony Sciscione¹², Dwight J Rouse¹³, Susan Ramin¹⁴; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and Obstetric-Fetal Pharmacology Research Units Network

Affiliations

¹ Department of Obstetrics and Gynecology and Reproductive Sciences and Pharmaceutical Sciences, University of Pittsburgh Schools of Medicine and Pharmacy, Pittsburgh, PA.
² The George Washington University Biostatistics Center, Washington, DC.
³ Department of Obstetrics and Gynecology, Wake Forest University Health Sciences, Winston-Salem, and University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Maternal-Fetal Medicine Units, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
⁵ Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI.
⁶ Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT.
⁷ Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY.
⁸ Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH.
⁹ Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI.
¹⁰ Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
¹¹ Department of Obstetrics and Gynecology, Case Western Reserve University-MetroHealth Medical Center, Cleveland, OH.
¹² Drexel University College of Medicine, Philadelphia, PA.
¹³ Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
¹⁴ Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, TX.

PMID: 24113254
PMCID: PMC3926421
DOI: 10.1016/j.ajog.2013.10.008

Randomized Controlled Trial

Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth

Steve N Caritis et al. Am J Obstet Gynecol. 2014 Feb.

. 2014 Feb;210(2):128.e1-6.

doi: 10.1016/j.ajog.2013.10.008. Epub 2013 Oct 7.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology and Reproductive Sciences and Pharmaceutical Sciences, University of Pittsburgh Schools of Medicine and Pharmacy, Pittsburgh, PA.
² The George Washington University Biostatistics Center, Washington, DC.
³ Department of Obstetrics and Gynecology, Wake Forest University Health Sciences, Winston-Salem, and University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Maternal-Fetal Medicine Units, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
⁵ Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI.
⁶ Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, UT.
⁷ Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY.
⁸ Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH.
⁹ Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI.
¹⁰ Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
¹¹ Department of Obstetrics and Gynecology, Case Western Reserve University-MetroHealth Medical Center, Cleveland, OH.
¹² Drexel University College of Medicine, Philadelphia, PA.
¹³ Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
¹⁴ Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, TX.

PMID: 24113254
PMCID: PMC3926421
DOI: 10.1016/j.ajog.2013.10.008

Abstract

Objective: 17-alpha hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation.

Study design: A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha hydroxyprogesterone caproate concentration.

Results: There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth (P = .03) and delivered at significantly earlier gestational ages (P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL.

Conclusion: Low plasma 17-alpha hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.

Keywords: 17-hydroxyprogesterone caproate concentration-response; dose response; pharmacodynamics.

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Figures

**Figure 1**
The data reflect the estimated distributions of gestational age at delivery for subjects with plasma 17-OHPC concentrations in the first quartile vs quartiles 2-4 combined.

**Figure 2**
Relationship between median 17-OHPC concentration from each quartile (Q1-Q4) of 17-OPHC concentrations and the rate of spontaneous preterm birth for each of those quartiles.

See this image and copyright information in PMC

References

1. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379–85. - PubMed
2. N Engl J Med. 2003;349:1299. Erratum in:
1. American College of Obstetricians and Gynecologists ACOG committee opinion no 419: use of progesterone to reduce preterm birth. Obstet Gynecol. 2008;112:963–5. - PubMed
1. [Accessed 4/26/2013]; www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid....
1. [Accessed 4/26/2013]; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati....
1. Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17α-hydroxyprogesterone caproate in the prevention of premature labor. N. Engl J Med. 1975;293:675–690. - PubMed

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Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth

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Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth

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